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1. Molecular characterization of Richter syndrome identifies de novo diffuse large B-cell lymphomas with poor prognosis

Author

Julien Broséus, Sébastien Hergalant, Julia Vogt, Eugen Tausch, Markus Kreuz, Anja Mottok, Christof Schneider, Caroline Dartigeas, Damien Roos-Weil, Anne Quinquenel, Charline Moulin, German Ott, Odile Blanchet, Cécile Tomowiak, Grégory Lazarian, Pierre Rouyer, Emil Chteinberg, Stephan H. Bernhart, Olivier Tournilhac, Guillaume Gauchotte, Sandra Lomazzi, Elise Chapiro, Florence Nguyen-Khac, Céline Chery, Frédéric Davi, Mathilde Hunault, Rémi Houlgatte, Andreas Rosenwald, Alain Delmer, David Meyre, Marie-Christine Béné, Catherine Thieblemont, Peter Lichter, Ole Ammerpohl, Jean-Louis Guéant, ICGC MMML-Seq Consortium, Romain Guièze, José Ignacio Martin-Subero, Florence Cymbalista, Pierre Feugier, Reiner Siebert, and Stephan Stilgenbauer

Subjects
Science
Abstract

Richter syndrome (RS) is the transformation of chronic lymphocytic leukaemia (CLL) into aggressive lymphoma, in most cases diffuse large B-cell lymphoma (DLBCL). Here, the authors characterize the DNA methylation and transcriptomic profiles of RS samples, find a clonally-related CLL epigenetic imprint, and develop classifiers for “RS-type” de novo DLBCLs.

Published
2023
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2. P600: DNA METHYLATION ANALYSIS OF B-CELL PROLYMPHOCYTIC LEUKEMIA REVEALS TWO EPIGENETIC SUBTYPES WITH DISTINCT BIOLOGICAL AND CLINICAL FEATURES

Author

Stella Charalampopoulou, Elise Chapiro, Ferran Nadeu, Thorsten Zenz, Silvia Beà, Damien Roos-Weil, Olivier Bernard, Santos A Susin, Estella Matutes, Elias Campo, Martí Duran-Ferrer, Florence Nguyen-Khac, and José Ignacio Martín-Subero

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2023
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3. P596: DELETION OF THE SHORT ARM OF CHROMOSOME 8 AND TNFRSF10B LOSS ASSOCIATE TO POOR PROGNOSIS AND DRUG RESISTANCE IN CHRONIC LYMPHOCYTIC LEUKEMIA

Author

Ludovic Jondreville, Lea Dehgane, Cecile Doualle, Luce Smagghe, Beatrice Grange, Frederic Davi, Leticia Koch Lerner, Delphine Garnier, Clotilde Bravetti, Olivier Tournilhac, Damien Roos-Weil, Marouane Boubaya, Elise Chapiro, Santos A Susin, and Florence Nguyen-Khac

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2023
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4. Retrospective analysis of a cohort of 41 de novo B-cell prolymphocytic leukemia patients: impact of genetics and targeted therapies (a FILO study)

Author

Caroline Algrin, Louis Pérol, Elise Chapiro, Lucile Baseggio, Karim Maloum, Catherine Settegrana, Jean-François Lesesve, Justine Siavellis, Alain Delmer, Anne-Sophie Michallet, Emmanuelle Ferrant, Pierre Feugier, Cécile Tomowiak, Annie Brion, David Ghez, Luc-Matthieu Fornecker, Sarah Ivanoff, Stéphanie Struski, Laurent Sutton, Isabelle Radford-Weiss, Virginie Eclache, Christine Lefebvre, Véronique Leblond, Florence Nguyen-Khac, and Damien Roos-Weil

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2022
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5. The Value of Neutrophil Gelatinase-Associated Lipocalin Receptor as a Novel Partner of CD38 in Chronic Lymphocytic Leukemia: From an Adverse Prognostic Factor to a Potential Pharmacological Target?

Author

Brigitte Bauvois, Elise Chapiro, Claire Quiney, Karim Maloum, Santos A. Susin, and Florence Nguyen-Khac

Subjects
CLL, CD38, NGAL-R, SLC22A17, relapse, remission, Biology (General), QH301-705.5
Abstract

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of neoplastic B lymphocytes that escape death, and correlates with the expression of negative prognostic markers such as the CD38 antigen. Although certain new drugs approved by the US Food and Drug Administration improve the clinical outcome of CLL patients, drug resistance and disease relapse still occur. Like CD38, neutrophil gelatinase-associated lipocalin receptor (NGAL-R) is frequently overexpressed in CLL cells. Here, we evaluated the concomitant surface expression of NGAL-R and CD38 in leukemic blood cells from 52 CLL patients (37 untreated, 8 in clinical remission, and 7 relapsed). We provide evidence of a positive correlation between NGAL-R and CD38 levels both in the interpatient cohorts (p < 0.0001) and in individual patients, indicating a constitutive association of NGAL-R and CD38 at the cell level. Patients with progressing CLL showed a time-dependent increase in NGAL-R/CD38 levels. In treated CLL patients who achieved clinical remission, NGAL-R/CD38 levels were decreased, and were significantly lower than in the untreated and relapsed groups (p < 0.02). As NGAL-R and CD38 participate in CLL cell survival, envisioning their simultaneous inhibition with bispecific NGAL-R/CD38 antibodies capable of inducing leukemic cell death might provide therapeutic benefit for CLL patients.

Published
2023
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6. Inflammation in Waldenström macroglobulinemia is associated with 6q deletion and need for treatment initiation

Author

Nathalie Forgeard, Marine Baron, Jonathan Caron, Clementine Boccon-Gibod, Daphne Krzisch, Nayara Guedes, Veronique Morel, Nathalie Jacque, Maya Ouzegdouh, Sylvain Choquet, Clotilde Bravetti, Florence Nguyen-Khac, Elise Chapiro, Veronique Leblond, and Damien Roos-Weil

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2022
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7. Targeting chronic lymphocytic leukemia with N-methylated thrombospondin-1–derived peptides overcomes drug resistance

Author

Elodie Pramil, Linda Herbi Bastian, Thomas Denèfle, Fariba Nemati, Malina Xiao, Eva Lardé, Karim Maloum, Damien Roos-Weil, Elise Chapiro, Magali Le Garff-Tavernier, Frédéric Davi, Didier Decaudin, Marika Sarfati, Florence Nguyen-Khac, Hélène Merle-Béral, Philippe Karoyan, and Santos A. Susin

Subjects
Specialties of internal medicine, RC581-951
Abstract

Abstract: Chronic lymphocytic leukemia (CLL), the most common adulthood leukemia in Western countries, is a very heterogeneous disease characterized by a peripheral accumulation of abnormal CD5+ B lymphocytes in the immune system. Despite new therapeutic developments, there remains an unmet medical need for CLL. Here, we demonstrate that the use of N-methylated thrombospondin-1 (TSP-1)–derived peptides is an efficient way to kill the malignant CLL cells, including those from high-risk individuals with poor clinical prognosis, del11q, del17p, 2p gain, or complex karyotype. PKT16, our hit N-methylated peptide, triggers the elimination of the leukemic cells, sparing the nontumor cells, including the hematopoietic precursors, and reduces the in vivo tumor burden of a CLL-xenograft mice model. A complementary analysis underscores the improved cytotoxic efficiency of PKT16 compared with the previously described TSP-1–derived probes, such as PKHB1. PKT16 elicits an original caspase-independent programmed necrotic mode of cell death, different from necroptosis or ferroptosis, implicating an intracellular Ca2+ deregulation that provokes mitochondrial damage, cell cycle arrest, and the specific death of the malignant CLL cells. The activation of the Gαi proteins and the subsequent drop of cyclic adenosine monophosphate levels and protein kinase A activity regulate this cytotoxic cascade. Remarkably, PKT16 induces the molecular hallmarks of immunogenic cell death, as defined by the calreticulin plasma membrane exposure and the release of adenosine triphosphate and high-mobility group box 1 protein from the dying CLL cells. Thus, PKT16 appears to be able to stimulate an anticancer in vivo immune response. Collectively, our results pave the way toward the development of an efficient strategy against CLL.

Published
2019
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8. Gain of the short arm of chromosome 2 (2p gain) has a significant role in drug‐resistant chronic lymphocytic leukemia

Author

Fotini Kostopoulou, Clementine Gabillaud, Elise Chapiro, Beatrice Grange, Julie Tran, Simon Bouzy, Michael Degaud, Hussein Ghamlouch, Magali Le Garff‐Tavernier, Karim Maloum, Sylvain Choquet, Veronique Leblond, Jean Gabarre, Anne Lavaud, Veronique Morel, Damien Roos‐Weil, Madalina Uzunov, Romain Guieze, Olivier A. Bernard, Santos A. Susin, Olivier Tournilhac, Florence Nguyen‐Khac, and the French Innovative Leukemia Organization (FILO) group

Subjects
2p gain, chronic lymphocytic leukemia, drug resistance, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract The different types of drug resistance encountered in chronic lymphocytic leukemia (CLL) cannot be fully accounted for by the 17p deletion (and/or TP53 mutation), a complex karyotype (CK), immunoglobulin heavy‐chain variable region genes (IGHV) status and gene mutations. Hence, we sought to assess the associations between recurrent genomic abnormalities in CLL and the disease's development and outcome. To this end, we analyzed 64 samples from patients with CLL and gain of the short arm of chromosome 2 (2p+), which is frequent in late‐stage and relapsed/refractory CLL. We found that fludarabine/cyclophosphamide/rituximab (a common first‐line treatment in CLL) is not effective in removing the 2p+ clone ‐ even in samples lacking a CK, the 17p deletion or unmutated IGHV. Our results suggest strongly that patients with CLL should be screened for 2p+ (using karyotyping and fluorescence in situ hybridization) before a treatment option is chosen. Longer follow‐up is now required to evaluate bendamustine‐rituximab, ibrutinib, and idelalisib‐rituximab treatments.

Published
2019
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10. The presence of a chromosomal abnormality in cytopenia without dysplasia identifies a category of high‐risk clonal cytopenia of unknown significance

Author

Victor-Emmanuel, Brett, Nicolas, Lechevalier, Franck, Trimoreau, Charles, Dussiau, Sophie, Dimicoli-Salazar, Lucie, Coster, Isabelle, Luquet, Nathalie, Nadal, Bénédicte, Ribourtout, Elise, Chapiro, Christine, Lefebvre, Sylvie, Tondeur, Estelle, Balducci, Florence, Nguyen-Khac, Claire, Borie, Isabelle, Radford-Weiss, Carole, Barin, Virginie, Eclache, Olivier, Mansier, and Audrey, Bidet

Subjects
Chromosome Aberrations, Cancer Research, Myelodysplastic Syndromes, Hematologic Neoplasms, Mutation, Genetics, Humans, Chromosome Disorders, Anemia
Abstract

Myelodysplastic syndromes (MDS) are hematological malignancies classically defined by the presence of cytopenia(s) and dysmorphic myeloid cells. It is now known that MDS can be preceded by a pre-malignant condition called clonal cytopenia of unknown significance (CCUS), which associates a clonality marker with cytopenia in the absence of criteria of dysplasia. However, to date, it is not clear whether chromosomal abnormalities should be considered in the definition of CCUS or if they carry a prognostic impact in CCUS patients. In this study, we analyzed the clinico-biological features and outcomes of 34 patients who presented with one or more cytopenias, an absence of significant dysplasia, and a presence of a chromosomal abnormality (CA). We named this entity chromosomal abnormality with cytopenia of undetermined significance (CACtUS). We show that these patients are slightly older than MDS patients and that they more frequently presented with normocytic anemia. Most CACtUS patients exhibited only one unbalanced CA. The number and type of mutations were comparable between CACtUS patients and MDS patients. Regardless of the cytogenetic abnormality, the clinicobiological characteristics, overall survival, and risk of progression to high-risk (HR) MDS were similar between CACtUS patients and low-risk MDS patients. Thus, we suggest that CACtUS patients can be considered as HR-CCUS and should receive the follow-up regimen recommended for MDS patients.

Published
2022

12. Poor prognosis of chromosome 7 clonal aberrations in Philadelphia-negative metaphases and relevance of potential underlying myelodysplastic features in chronic myeloid leukemia

Author

Audrey Bidet, Stéphanie Dulucq, Thomas Smol, Alice Marceau-Renaut, Stéphane Morisset, Valérie Coiteux, Marie-Pierre Noël-Walter, Franck-Emmanuel Nicolini, Isabelle Tigaud, Isabelle Luquet, Stéphanie Struski, Baptiste Gaillard, Dominique Penther, Sylvie Tondeur, Nathalie Nadal, Eric Hermet, Lauren Véronèse, Delphine Réa, Carine Gervais, Olivier Theisen, Christine Terré, Pascale Cony-Makhoul, Christine Lefebvre, Jean-Baptiste Gaillard, Isabelle Radford, Anne-Laure Vervaeke, Carole Barin, Elise Chapiro, Florence Nguyen-Khac, Gabriel Etienne, Claude Preudhomme, François Xavier Mahon, and Catherine Roche-Lestienne

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Clonal chromosome abnormalities in Philadelphia-negative cells could concern chronic myeloid leukemia patients treated by tyrosine kinase inhibitors. The European LeukemiaNet distinguishes -7/del(7q) abnormalities as a “warning”. However, the impact of clonal chromosome abnormalities, and specifically those of -7/del(7q), in Philadelphia-negative cells on clinical outcomes is unclear and based on case-reports showing morphological dysplasia and increased risk of acute myeloid leukemia, suggesting the coexistence of chronic myeloid leukemia and high-risk myelodysplastic syndrome. The aim of this study was to determine whether the impact of -7/del(7q) clonal chromosome abnormalities in Philadelphia-negative cells on the clinical outcome is different from that of other types of abnormalities, and we argue for an underlying associated high-risk myelodysplastic syndrome. Among 102 chronic myeloid leukemia patients with clonal chromosome abnormalities in Philadelphia-negative cells with more than a median of 6 years of follow up, patients with -7/del(7q) more frequently had signs of dysplasia, a lower cumulative incidence of deep molecular response and often needed further treatment lines, with the consequent impact on event-free and progression-free survival. Morphological features of dysplasia are associated with myelodysplastic syndrome/acute myeloid leukemia mutations and compromise the optimal response to tyrosine kinase inhibitors, irrespectively of the type of clonal chromosome abnormalities in Philadelphia-negative cells. However, mutation patterns determined by next-generation sequencing could not clearly explain the underlying high-risk disease. We hereby confirm the pejorative prognostic value of -7/del(7q) clonal chromosome abnormalities in Philadelphia-negative cells and suggest that myelodysplastic features constitute a warning signal that response to tyrosine kinase inhibitors may be less than optimal.

Published
2019
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13. Myeloid malignancies with translocation t(4;12)(q11‐13;p13): molecular landscape, clonal hierarchy and clinical outcomes

Author

François Lifermann, Jean-Alain Martignoles, Anne Quinquenel, Vincent Parinet, Christine Lefebvre, Pierre Hirsch, Mélanie Martin, Sabine Defasque, Florence Nguyen-Khac, Matthieu Decamp, Laurence Simon, Dominique Penther, Nadia Ali-Ammar, Elise Chapiro, Odile Maarek, Chrystele Bilhou-Nabera, Baptiste Gaillard, Agathe Maillon, Jean-Baptiste Micol, Marine Baron, Nathalie Auger, Stéphanie Struski, Damien Roos-Weil, Sylvie Tondeur, Marie-Joelle Mozziconacci, Audrey Bidet, Service d'Hématologie clinique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Hôpital Robert Debré, Service d'Hémato-oncologie [CHU Saint-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire [Grenoble] (CHU), Laboratoire CERBA [Saint Ouen l'Aumône], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre Hospitalier Universitaire de Reims (CHU Reims), Service de Génétique [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Centre Hospitalier de Dax, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Service d'immunologie et hématologies biologiques [CHU Saint-Antoine], Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), HAL-SU, Gestionnaire, École Pratique des Hautes Études (EPHE), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Oncology, Myeloid, [SDV]Life Sciences [q-bio], Chromosomal translocation, Translocation, Genetic, chemistry.chemical_compound, 0302 clinical medicine, hemic and lymphatic diseases, 12), In Situ Hybridization, Fluorescence, Aged, 80 and over, CHIC2, Middle Aged, Immunohistochemistry, 3. Good health, [SDV] Life Sciences [q-bio], Leukemia, Myeloid, Acute, medicine.anatomical_structure, RUNX1, 030220 oncology & carcinogenesis, Cytogenetic Analysis, Cohort, Molecular Medicine, Female, Original Article, Chromosomes, Human, Pair 4, medicine.medical_specialty, IDH1, 03 medical and health sciences, Internal medicine, Biomarkers, Tumor, medicine, Humans, Genetic Predisposition to Disease, acute myeloid leukaemia, Genetic Association Studies, Aged, Chromosome Aberrations, Chromosomes, Human, Pair 12, Myeloproliferative Disorders, business.industry, Myelodysplastic syndromes, Original Articles, ETV6, Cell Biology, medicine.disease, myelodysplastic syndrome, t(4, chemistry, Fusion transcript, Myelodysplastic Syndromes, prognosis, business, 030215 immunology
Abstract

International audience; Translocation t(4;12)(q11-13;p13) is a recurrent but very rare chromosomal aberration in acute myeloid leukaemia (AML) resulting in the non-constant expression of a CHIC2/ETV6 fusion transcript. We report clinico-biological features, molecular characteristics and outcomes of 21 cases of t(4;12) including 19 AML and two myelodysplastic syndromes (MDS). Median age at the time of t(4;12) was 78 years (range, 56–88). Multilineage dysplasia was described in 10 of 19 (53%) AML cases and CD7 and/or CD56 expression in 90%. FISH analyses identified ETV6 and CHIC2 region rearrangements in respectively 18 of 18 and 15 of 17 studied cases. The t(4;12) was the sole cytogenetic abnormality in 48% of cases. The most frequent associated mutated genes were ASXL1 (n = 8/16, 50%), IDH1/2 (n = 7/16, 44%), SRSF2 (n = 5/16, 31%) and RUNX1 (n = 4/16, 25%). Interestingly, concurrent FISH and molecular analyses showed that t(4;12) can be, but not always, a founding oncogenic event. Median OS was 7.8 months for the entire cohort. In the 16 of 21 patients (76%) who received antitumoral treatment, overall response and first complete remission rates were 37% and 31%, respectively. Median progression-free survival in responders was 13.7 months. Finally, t(4;12) cases harboured many characteristics of AML with myelodysplasia-related changes (multilineage dysplasia, MDS-related cytogenetic abnormalities, frequent ASXL1 mutations) and a poor prognosis.

Published
2021

15. The complex karyotype and chronic lymphocytic leukemia: prognostic value and diagnostic recommendations

Author

Daphné Krzisch, Ludovic Jondreville, Elise Chapiro, and Florence Nguyen-Khac

Subjects
Oncology, medicine.medical_specialty, Chronic lymphocytic leukemia, Abnormal Karyotype, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Chemoimmunotherapy, hemic and lymphatic diseases, Internal medicine, Complex Karyotype, medicine, Humans, Neoplasm, Survival rate, business.industry, Myeloid leukemia, Hematology, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Survival Rate, Chromosome 17 (human), Leukemia, Hematologic Neoplasms, 030220 oncology & carcinogenesis, Tumor Suppressor Protein p53, business, Chromosomes, Human, Pair 17, 030215 immunology
Abstract

Chromosomal abnormalities are frequently observed in patients with chronic lymphocytic leukemia (CLL) and have prognostic value. Deletions of the short arm of chromosome 17 (and/or mutations TP53) predict resistance to chemoimmunotherapy and shorter progression-free survival after targeted therapies. Although the complex karyotype (CK) is strongly predictive of a poor prognosis in hematologic malignancies such acute myeloid leukemia or myelodysplastic syndrome, its value in CLL is subject to debate. Here, we review the literature on the CK in CLL and examine its prognostic value with different treatments. We also propose a standardized method for defining a CK in all types of hematopoietic neoplasm.

Published
2020

16. CD47 agonist peptides induce programmed cell death in refractory chronic lymphocytic leukemia B cells via PLCγ1 activation: evidence from mice and humans.

Author

Ana-Carolina Martinez-Torres, Claire Quiney, Tarik Attout, Heloïse Boullet, Linda Herbi, Laura Vela, Sandrine Barbier, Danielle Chateau, Elise Chapiro, Florence Nguyen-Khac, Frédéric Davi, Magali Le Garff-Tavernier, Roba Moumné, Marika Sarfati, Philippe Karoyan, Hélène Merle-Béral, Pierre Launay, and Santos A Susin

Subjects
Medicine
Abstract

BackgroundChronic lymphocytic leukemia (CLL), the most common adulthood leukemia, is characterized by the accumulation of abnormal CD5+ B lymphocytes, which results in a progressive failure of the immune system. Despite intense research efforts, drug resistance remains a major cause of treatment failure in CLL, particularly in patients with dysfunctional TP53. The objective of our work was to identify potential approaches that might overcome CLL drug refractoriness by examining the pro-apoptotic potential of targeting the cell surface receptor CD47 with serum-stable agonist peptides.Methods and findingsIn peripheral blood samples collected from 80 patients with CLL with positive and adverse prognostic features, we performed in vitro genetic and molecular analyses that demonstrate that the targeting of CD47 with peptides derived from the C-terminal domain of thrombospondin-1 efficiently kills the malignant CLL B cells, including those from high-risk individuals with a dysfunctional TP53 gene, while sparing the normal T and B lymphocytes from the CLL patients. Further studies reveal that the differential response of normal B lymphocytes, collected from 20 healthy donors, and leukemic B cells to CD47 peptide targeting results from the sustained activation in CLL B cells of phospholipase C gamma-1 (PLCγ1), a protein that is significantly over-expressed in CLL. Once phosphorylated at tyrosine 783, PLCγ1 enables a Ca2+-mediated, caspase-independent programmed cell death (PCD) pathway that is not down-modulated by the lymphocyte microenvironment. Accordingly, down-regulation of PLCγ1 or pharmacological inhibition of PLCγ1 phosphorylation abolishes CD47-mediated killing. Additionally, in a CLL-xenograft model developed in NOD/scid gamma mice, we demonstrate that the injection of CD47 agonist peptides reduces tumor burden without inducing anemia or toxicity in blood, liver, or kidney. The limitations of our study are mainly linked to the affinity of the peptides targeting CD47, which might be improved to reach the standard requirements in drug development, and the lack of a CLL animal model that fully mimics the human disease.ConclusionsOur work provides substantial progress in (i) the development of serum-stable CD47 agonist peptides that are highly effective at inducing PCD in CLL, (ii) the understanding of the molecular events regulating a novel PCD pathway that overcomes CLL apoptotic avoidance, (iii) the identification of PLCγ1 as an over-expressed protein in CLL B cells, and (iv) the description of a novel peptide-based strategy against CLL.

Published
2015
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17. Cytogenetic and molecular abnormalities in Waldenström's macroglobulinemia patients: correlations and prognostic impact

Author

Nayara Guedes, Santos A. Susin, Damien Roos-Weil, Clotilde Bravetti, Marine Baron, Luce Smagghe, Marine Armand, Veronique Leblond, Jonathan Caron, Florence Nguyen-Khac, Frederic Davi, Olivier A. Bernard, Clémentine Boccon‐Gibod, Elise Chapiro, Daphné Krzisch, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Gustave Roussy (IGR), Dynamique moléculaire de la transformation hématopoïétique (Dynamo), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, HAL-SU, Gestionnaire, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP)

Subjects
Adult, Male, medicine.medical_specialty, complex karyotype, medicine.medical_treatment, CXCR4, Gastroenterology, cytogenetic abnormalities, Cytogenetics, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Aged, Retrospective Studies, Aged, 80 and over, Chromosome Aberrations, Chemotherapy, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Macroglobulinemia, Waldenstrom macroglobulinemia, Retrospective cohort study, Karyotype, Hematology, Middle Aged, CD79A, medicine.disease, mutations, 3. Good health, 030220 oncology & carcinogenesis, Mutation, Waldenström, Female, prognosis, Waldenstrom Macroglobulinemia, business, Trisomy, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract

While Waldenstrom macroglobulinemia (WM) is characterized by an almost unifying mutation in MYD88, clinical presentation at diagnosis and response to therapy can be widely different among WM patients. Current prognostic tools only partially address this clinical heterogeneity. Limited data compiling both molecular and cytogenetic information have been used in risk prognostication in WM. To investigate the clinical impact of genetic alterations in WM, we evaluated cytogenetic and molecular abnormalities by chromosome banding analyses (CBA), FISH and targeted NGS in a retrospective cohort of 239 WM patients, including 187 patients treated by first-line chemotherapy or immunochemotherapy. Most frequent mutations were identified in MYD88 (93%), CXCR4 (29%), MLL2 (11%), ARID1A (8%), TP53 (8%), CD79A/B (6%), TBL1XR1 (4%) and SPI1 (4%). The median number of cytogenetic abnormalities was two (range, 0-22). Main cytogenetic abnormalities were 6q deletion (del6q) (27%), trisomy 4 (tri4) (12%), tri18 (11%), del13q (11%), tri12 (7.5%) and del17p (7%). Complex karyotype (CK) was observed in 15% (n=31) of cases, including 5% (n=12) of highly CK (high-CK). TP53 abnormalities (TP53abn) were present in 15% of evaluable patients. TP53abn and del6q were associated with CK/high-CK (P

Published
2021

18. Clinical, biological, and molecular genetic features of Richter syndrome and prognostic significance: a study of the French Innovative Leukemia Organization

Author

Reiner Siebert, Anne Quinquenel, Romain Guieze, Catherine Thieblemont, Frederic Davi, Caroline Dartigeas, Sébastien Hergalant, Mathilde Hunault, Florence Cymbalista, Christof Schneider, Marie-Christine Béné, Cécile Tomowiak, Thomas Remen, Kamel Laribi, Damien Roos-Weil, Julien Broséus, Gregory Lazarian, Francis Guillemin, Odile Blanchet, Florian Bouclet, Elise Chapiro, Eugen Tausch, Stephan Stilgenbauer, Sandra Lomazzi, Florence Nguyen-Khac, Pierre Feugier, Charline Moulin, Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre d'investigation clinique - Epidémiologie clinique [Nancy] (CIC-EC), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département Méthodologie Promotion Investigation [CHRU Nancy] (MPI), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Hospitalier Universitaire de Reims (CHU Reims), Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Ulm - Ulm University [Ulm, Allemagne], Adaptateurs de signalisation en hématologie (ASIH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre de Ressources Biologiques - [Nancy] (CRB Nancy), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Avicenne [AP-HP], Centre Hospitalier Le Mans (CH Le Mans), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hergalant, Sébastien, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
Oncology, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.medical_specialty, Richter syndrome, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Medicine, Humans, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 0303 health sciences, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Hematology, medicine.disease, Prognosis, Survival Analysis, 3. Good health, [STAT] Statistics [stat], [STAT]Statistics [stat], Leukemia, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 030220 oncology & carcinogenesis, Cytogenetic Analysis, Mutation, Disease Progression, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, Lymphoma, Large B-Cell, Diffuse, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business
Abstract

International audience

Published
2021

19. Chromosomal aberrations and their prognostic value in a series of 174 untreated patients with Waldenström's macroglobulinemia

Author

Florence Nguyen-Khac, Jerome Lambert, Elise Chapiro, Aurore Grelier, Sarah Mould, Carole Barin, Agnes Daudignon, Nathalie Gachard, Stéphanie Struski, Catherine Henry, Dominique Penther, Hossein Mossafa, Joris Andrieux, Virginie Eclache, Chrystèle Bilhou-Nabera, Isabelle Luquet, Christine Terre, Laurence Baranger, Francine Mugneret, Jean Chiesa, Marie-Joelle Mozziconacci, Evelyne Callet-Bauchu, Lauren Veronese, Hélène Blons, Roger Owen, Julie Lejeune, Sylvie Chevret, Hélène Merle-Beral, and Véronique Leblond

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Waldenström's macroglobulinemia is a disease of mature B cells, the genetic basis of which is poorly understood. Few recurrent chromosomal abnormalities have been reported, and their prognostic value is not known. We conducted a prospective cytogenetic study of Waldenström's macroglobulinemia and examined the prognostic value of chromosomal aberrations in an international randomized trial. The main aberrations were 6q deletions (30%), trisomy 18 (15%), 13q deletions (13%), 17p (TP53) deletions (8%), trisomy 4 (8%), and 11q (ATM) deletions (7%). There was a significant association between trisomy of chromosome 4 and trisomy of chromosome 18. Translocations involving the IGH genes were rare (

Published
2013
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20. [Watch out for a second train]

Author

Adélaïde Toutée, Myrto Costopoulos, Clotilde Bravetti, Frederic Davi, Elise Chapiro, Michaël Degaud, Agathe Maillon, Sylvain Choquet, Magali Le Garff-Tavernier, Anne Lavaud, Anne de Septenville, Karim Maloum, and Frédéric Charlotte

Subjects
Male, Pathology, medicine.medical_specialty, Vision, Low, Monoclonal Gammopathy of Undetermined Significance, Flow cytometry, Immunophenotyping, Diagnosis, Differential, Nasal fossae, Medicine, Humans, B cell, Aged, Carcinoma, Transitional Cell, Incidental Findings, Hematologic Tests, medicine.diagnostic_test, business.industry, Eye Neoplasms, Waldenstrom macroglobulinemia, General Medicine, medicine.disease, medicine.anatomical_structure, Immunoglobulin M, Urinary Bladder Neoplasms, Lymphoma, Large B-Cell, Diffuse, Urothelium, Waldenstrom Macroglobulinemia, business, Diffuse large B-cell lymphoma
Abstract

We report the case of a man with a primary diagnosis of Waldenstrom macroglobulinemia. He secondarily presented a diffuse large B cell lymphoma (DLBCL) located in the nasal fossae, which relapsed later in the eye. The diagnosis of these two malignancies is based on a multidisciplinary biological approach using new sensitive and specific techniques. These techniques revealed that the two diseases harbor different B cell clones, indicating a distinct origin. This observation highlights the importance of targeted biological techniques for the diagnosis of these two rare hemopathies. It also shows that it is possible to prove the independent nature of the two tumor clones, thus allowing optimized therapeutic management.

Published
2020

21. Relation of Neutrophil Gelatinase-Associated Lipocalin Overexpression to the Resistance to Apoptosis of Tumor B Cells in Chronic Lymphocytic Leukemia

Author

Ludovic Jondreville, Karim Maloum, Santos A. Susin, Brigitte Bauvois, Florence Nguyen-Khac, Claire Quiney, Elodie Pramil, Elise Chapiro, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Gestionnaire, HAL Sorbonne Université 5, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, 0301 basic medicine, Cancer Research, Programmed cell death, Chronic lymphocytic leukemia, [SDV.CAN]Life Sciences [q-bio]/Cancer, NGAL-R, Lipocalin, Peripheral blood mononuclear cell, lcsh:RC254-282, survival, Article, STAT3, 03 medical and health sciences, 0302 clinical medicine, remission, [SDV.CAN] Life Sciences [q-bio]/Cancer, immune system diseases, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], hemic and lymphatic diseases, medicine, NGAL, Autocrine signalling, neoplasms, relapse, biology, business.industry, apoptosis, Mcl-1, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Leukemia, 030104 developmental biology, Oncology, Apoptosis, 030220 oncology & carcinogenesis, biology.protein, Cancer research, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Antibody, business, CLL
Abstract

International audience; The resistance to apoptosis of chronic lymphocytic leukemia (CLL) cells partly results from the deregulated production of survival signals from leukemic cells. Despite the development of new therapies in CLL, drug resistance and disease relapse still occur. Recently, neutrophil gelatinase-associated lipocalin (NGAL), a secreted glycoprotein, has been suggested to have a critical role in the biology of tumors. Thus, we investigated the relevance of NGAL in CLL pathogenesis, analyzed the expression of its cellular receptor (NGAL-R) on malignant B cells and tested whether CLL cells are resistant to apoptosis through an autocrine process involving NGAL and NGAL-R. We observed that NGAL concentrations were elevated in the serum of CLL patients at diagnosis. After treatment (and regardless of the therapeutic regimen), serum NGAL levels normalized in CLL patients in remission but not in relapsed patients. In parallel, NGAL and NGAL-R were upregulated in leukemic cells from untreated CLL patients when compared to normal peripheral blood mononuclear cells (PBMCs), and returned to basal levels in PBMCs from patients in remission. Cultured CLL cells released endogenous NGAL. Anti-NGAL-R antibodies enhanced NGAL-R + leukemia cell death. Conversely, recombinant NGAL protected NGAL-R + CLL cells against apoptosis by activating a STAT3/Mcl-1 signaling pathway. Our results suggest that NGAL and NGAL-R, overexpressed in untreated CLL, participate in the deregulation of the apoptotic machinery in CLL cells, and may be potential therapeutic clues for CLL treatment.

Published
2020

22. Correction: Refinement of 1p36 Alterations Not Involving in Myeloid and Lymphoid Malignancies.

Author

Francois P. Duhoux, Geneviève Ameye, Virginie Lambot, Christian Herens, Frédéric Lambert, Sophie Raynaud, Iwona Wlodarska, Lucienne Michaux, Catherine Roche-Lestienne, Elise Labis, Sylvie Taviaux, Elise Chapiro, Florence Nguyen-Khac, Stéphanie Struski, Sophie Dobbelstein, Nicole Dastugue, Eric Lippert, Frank Speleman, Nadine Van Roy, An De Weer, Katrina Rack, Pascaline Talmant, Steven Richebourg, Francine Mugneret, Isabelle Tigaud, Marie-Joëlle Mozziconacci, Sophy Laibe, Nathalie Nadal, Christine Terré, Jeanne-Marie Libouton, Anabelle Decottignies, Miikka Vikkula, and Hélène A. Poirel

Subjects
Medicine, Science
Published
2011
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23. Refinement of 1p36 alterations not involving PRDM16 in myeloid and lymphoid malignancies.

Author

Francois P Duhoux, Geneviève Ameye, Virginie Lambot, Christian Herens, Frédéric Lambert, Sophie Raynaud, Iwona Wlodarska, Lucienne Michaux, Catherine Roche-Lestienne, Elise Labis, Sylvie Taviaux, Elise Chapiro, Florence Nguyen-Khac, Stéphanie Struski, Sophie Dobbelstein, Nicole Dastugue, Eric Lippert, Frank Speleman, Nadine Van Roy, An De Weer, Katrina Rack, Pascaline Talmant, Steven Richebourg, Francine Mugneret, Isabelle Tigaud, Marie-Joëlle Mozziconacci, Sophy Laibe, Nathalie Nadal, Christine Terré, Jeanne-Marie Libouton, Anabelle Decottignies, Miikka Vikkula, Hélène A Poirel, Groupe Francophone de Cytogénétique Hématologique (GFCH), and Belgian Cytogenetic Group for Hematology and Oncology (BCG-HO)

Subjects
Medicine, Science
Abstract

Fluorescence in situ hybridization was performed to characterize 81 cases of myeloid and lymphoid malignancies with cytogenetic 1p36 alterations not affecting the PRDM16 locus. In total, three subgroups were identified: balanced translocations (N = 27) and telomeric rearrangements (N = 15), both mainly observed in myeloid disorders; and unbalanced non-telomeric rearrangements (N = 39), mainly observed in lymphoid proliferations and frequently associated with a highly complex karyotype. The 1p36 rearrangement was isolated in 12 cases, mainly myeloid disorders. The breakpoints on 1p36 were more widely distributed than previously reported, but with identifiable rare breakpoint cluster regions, such as the TP73 locus. We also found novel partner loci on 1p36 for the known multi-partner genes HMGA2 and RUNX1. We precised the common terminal 1p36 deletion, which has been suggested to have an adverse prognosis, in B-cell lymphomas [follicular lymphomas and diffuse large B-cell lymphomas with t(14;18)(q32;q21) as well as follicular lymphomas without t(14;18)]. Intrachromosomal telomeric repetitive sequences were detected in at least half the cases of telomeric rearrangements. It is unclear how the latter rearrangements occurred and whether they represent oncogenic events or result from chromosomal instability during oncogenesis.

Published
2011
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24. Gain in the short arm of chromosome 2 (2p+) induces gene overexpression and drug resistance in chronic lymphocytic leukemia: analysis of the central role of XPO1

Author

Veronique Leblond, Elise Chapiro, Claude Lesty, Madalina Uzunov, N Bougacha, Santos A. Susin, Florence Nguyen-Khac, M-N Brunelle-Navas, A Cosson, M Le Garff-Tavernier, Y Landesman, P. Feugier, Laurent Sutton, Véronique Morel, Damien Roos-Weil, Boris Keren, Hélène Merle-Béral, H-A Cung, Frederik Damm, L Herbi, Karim Maloum, Julie Lejeune, Sylvain Choquet, Stéphane Leprêtre, Jérôme Lambert, Caroline Algrin, Clementine Gabillaud, and Frederic Davi

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, Chronic lymphocytic leukemia, Receptors, Cytoplasmic and Nuclear, Apoptosis, Drug resistance, Karyopherins, Biology, Fusion gene, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Gene, Regulation of gene expression, Hematology, Gene Expression Regulation, Leukemic, Triazoles, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Haematopoiesis, Leukemia, Hydrazines, 030104 developmental biology, Oncology, Drug Resistance, Neoplasm, Chromosomes, Human, Pair 2, 030220 oncology & carcinogenesis, Cancer research
Abstract

Gain in the short arm of chromosome 2 (2p+) induces gene overexpression and drug resistance in chronic lymphocytic leukemia: analysis of the central role of XPO1

Published
2017

25. Targeting chronic lymphocytic leukemia with N-methylated thrombospondin-1–derived peptides overcomes drug resistance

Author

Frederic Davi, Malina Xiao, Thomas Denèfle, Philippe Karoyan, Eva Lardé, Florence Nguyen-Khac, Santos A. Susin, Elise Chapiro, H. Merle-Beral, Damien Roos-Weil, Fariba Nemati, Karim Maloum, Didier Decaudin, Elodie Pramil, Magali Le Garff-Tavernier, Marika Sarfati, Linda Herbi Bastian, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université (SU), Université Sorbonne Paris Cité (USPC), Université Paris Descartes - Paris 5 (UPD5), Université Paris Diderot - Paris 7 (UPD7), Laboratoire des biomolécules (LBM UMR 7203), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Curie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], and Service d'Hématologie Clinique [CHU Pitié-Salpêtrière]

Subjects
Models, Molecular, Necroptosis, Chronic lymphocytic leukemia, [SDV]Life Sciences [q-bio], Antineoplastic Agents, Apoptosis, medicine.disease_cause, Thrombospondin 1, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, hemic and lymphatic diseases, Cell Line, Tumor, medicine, Cyclic AMP, Cytotoxic T cell, Animals, Humans, 030304 developmental biology, 0303 health sciences, Lymphoid Neoplasia, Cell Death, Chemistry, Molecular Mimicry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Cell Cycle Checkpoints, medicine.disease, Cyclic AMP-Dependent Protein Kinases, Leukemia, Lymphocytic, Chronic, B-Cell, Xenograft Model Antitumor Assays, 3. Good health, Mitochondria, Molecular mimicry, Leukemia, Disease Models, Animal, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Caspases, Cancer research, Immunogenic cell death, Female, CD5, Peptides, Signal Transduction
Abstract

International audience; Chronic lymphocytic leukemia (CLL), the most common adulthood leukemia in Western countries, is a very heterogeneous disease characterized by a peripheral accumulation of abnormal CD5+ B lymphocytes in the immune system. Despite new therapeutic developments, there remains an unmet medical need for CLL. Here, we demonstrate that the use of N-methylated thrombospondin-1 (TSP-1)-derived peptides is an efficient way to kill the malignant CLL cells, including those from high-risk individuals with poor clinical prognosis, del11q, del17p, 2p gain, or complex karyotype. PKT16, our hit N-methylated peptide, triggers the elimination of the leukemic cells, sparing the nontumor cells, including the hematopoietic precursors, and reduces the in vivo tumor burden of a CLL-xenograft mice model. A complementary analysis underscores the improved cytotoxic efficiency of PKT16 compared with the previously described TSP-1-derived probes, such as PKHB1. PKT16 elicits an original caspase-independent programmed necrotic mode of cell death, different from necroptosis or ferroptosis, implicating an intracellular Ca2+ deregulation that provokes mitochondrial damage, cell cycle arrest, and the specific death of the malignant CLL cells. The activation of the Gαi proteins and the subsequent drop of cyclic adenosine monophosphate levels and protein kinase A activity regulate this cytotoxic cascade. Remarkably, PKT16 induces the molecular hallmarks of immunogenic cell death, as defined by the calreticulin plasma membrane exposure and the release of adenosine triphosphate and high-mobility group box 1 protein from the dying CLL cells. Thus, PKT16 appears to be able to stimulate an anticancer in vivo immune response. Collectively, our results pave the way toward the development of an efficient strategy against CLL.

Published
2019

26. Genetic characterization of B-cell prolymphocytic leukemia: a prognostic model involving MYC and TP53

Author

Olivier A. Bernard, Elodie Pramil, Florence Nguyen-Khac, Clementine Gabillaud, Nathalie Nadal, Elise Chapiro, Simon Bouzy, Frederic Davi, Stéphanie Struski, Damien Roos-Weil, Christine Lefebvre, Evelyne Callet-Bauchu, Magali Le Garff-Tavernier, Philippe Dessen, Virginie Eclache, Caroline Algrin, Jean-François Lesesve, Veronique Leblond, Lena Wagner, Claude Lesty, Sandra Fert-Ferrer, Melanie Yon, Ludovic Jondreville, Nathalie Auger, Jean Gabarre, Antoine Ittel, Marie-Agnès Collonge-Rame, Karim Maloum, Clémentine Dillard, M'Boyba Diop, Catherine Settegrana, Thorsten Zenz, Sebastian Scheinost, Baptiste Gaillard, Benoit Quilichini, Isabelle Radford-Weiss, Marc Muller, Nathalie Droin, Lucile Baseggio, Santos A. Susin, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Institut Gustave Roussy (IGR), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hospices Civils de Lyon (HCL), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hématopoïèse normale et pathologique (U1170 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), Hôpital Robert Debré, Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Strasbourg, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Métropole Savoie [Chambéry], CHU Necker - Enfants Malades [AP-HP], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Universität Zürich [Zürich] = University of Zurich (UZH), Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Hospitalier Mutualiste [Grenoble] (GHM), Hôpital Avicenne [AP-HP], Service d'hématologie [Reims], Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Service de Génétique [CHRU Nancy], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Eurofins Biomnis, Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], and University hospital of Zurich [Zurich]

Subjects
0301 basic medicine, Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Immunology, Chromosomal translocation, Biology, Biochemistry, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, 0302 clinical medicine, SETD2, B-cell prolymphocytic leukemia, medicine, Humans, Prolymphocytic leukemia, Aged, Aged, 80 and over, Chromosome Aberrations, Leukemia, Prolymphocytic, B-Cell, Cytogenetics, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Hematology, Middle Aged, medicine.disease, Prognosis, 3. Good health, Leukemia, 030104 developmental biology, Cytogenetic Analysis, Chromosome abnormality, Cancer research, Female, Tumor Suppressor Protein p53, IGHV@, 030215 immunology
Abstract

International audience; B-cell prolymphocytic leukemia (B-PLL) is a rare hematological disorder whose underlying oncogenic mechanisms are poorly understood. Our cytogenetic and molecular assessment of 34 patients with B-PLL revealed several disease-specific features and potential therapeutic targets. The karyotype was complex ({greater than or equal to}3 abnormalities) in 73% of the patients and highly complex (>5 abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving MYC [t(MYC)] (62%), deletion (del)17p (38%), trisomy (tri)18 (30%), del13q (29%), tri3 (24%), tri12 (24%), and del8p (23%). Twenty-six of the 34 patients (76%) exhibit MYC aberration, resulting from mutually exclusive translocations or gains. Whole-exome sequencing revealed frequent mutations in TP53, MYD88, BCOR, MYC, SF3B1, SETD2, CHD2, CXCR4, and BCLAF1 The majority of B-PLL used the IGHV3 or IGHV4 subgroups (89%), and displayed significantly mutated IGHV genes (79%). We identified three distinct cytogenetic risk groups: low-risk (no MYC aberration), intermediate-risk (MYC aberration but no del17p), and high-risk (MYC aberration and del17p) (p=.0006). In vitro drug response profiling revealed that the combination of a B-cell receptor or BCL2 inhibitor with OTX015 (a bromodomain and extra-terminal motif (BET) inhibitor targeting MYC) was associated with significantly lower viability of B-PLL cells harboring a t(MYC). We conclude that cytogenetic analysis is a useful diagnostic and prognostic tool in B-PLL. Targeting MYC may be a useful treatment option in this disease.

Published
2019

27. Isolated isochromosomes i(X)(p10) and idic(X)(q13) are associated with myeloid malignancies and dysplastic features

Author

Isabelle Rafdord-Weiss, Dominique Penther, Carole Barin, Baptiste Gaillard, Benoit Quilichini, Catherine Roche-Lestienne, Pascaline Etancelin, Christine Lefebvre, Daniel Lusina, Gwenaël Nadeau, Francine Mugneret, Catherine Godon, Virginie Eclache, Florence Nguyen-Khac, Yann Ferret, M J Mozziconacci, Antoine Ittel, Nathalie Nadal, Audrey Bidet, Gwendoline Soler, Elise Chapiro, Groupe Francophone de Cytogénétique Hématologique, Agnès Daudignon, Steven Richebourg, Pierre-Julien Viailly, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Service d'hématologie biologique [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Dpt hématologie [CHU Bordeaux], CHU Bordeaux [Bordeaux], Hôpital de la Timone [CHU - APHM] (TIMONE), Thales Communications [Colombes], THALES, CHU Bretonneau, CHU Clermont-Ferrand, Centre Hospitalier de Valenciennes, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Service d'hématologie biologique [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Service d'hématologie biologique [Nantes] (Cytologie Hématologique), Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôtel-Dieu de Nantes, Service de Cytogénétique, Centre hospitalier de Valence, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Cytogenetics [Québec, Canada], Centre Hospitalier Universitaire du Québec (CHUQ)-Hôpital du Saint-Sacrement [CHU Québec] (HSS), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Picardie Jules Verne (UPJV), and Hôpital Avicenne [AP-HP]

Subjects
Male, Myeloid, [SDV]Life Sciences [q-bio], Isochromosome, Dioxygenases, 03 medical and health sciences, 0302 clinical medicine, Age Distribution, Bone Marrow, Proto-Oncogene Proteins, medicine, Neoplasm, Humans, Sex Distribution, Gene, ComputingMilieux_MISCELLANEOUS, Aged, Chromosomes, Human, X, business.industry, Follow up studies, Neoplasms, Second Primary, Hematology, Middle Aged, medicine.disease, 3. Good health, Neoplasm Proteins, DNA-Binding Proteins, Isochromosomes, Leukemia, medicine.anatomical_structure, Leukemia, Myeloid, 030220 oncology & carcinogenesis, Myelodysplastic Syndromes, Mutation (genetic algorithm), Mutation, Cancer research, Age distribution, Female, business, 030215 immunology, Follow-Up Studies, Genes, Neoplasm
Abstract

International audience

Published
2019

28. Automated differential white blood cell count and cytological analysis can detect near-tetraploid cells in chronic lymphoproliferative disorders

Author

Catherine Settegrana, Frederic Davi, Florence Nguyen-Khac, Adrien Cosson, Sylvain Choquet, Karim Maloum, Veronique Leblond, Elise Chapiro, Corinne Frere, CHU Pitié-Salpêtrière [APHP], Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Service d'Hématologie Clinique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Service d'Hématologie clinique [CHU Pitié-Salpêtrière]

Subjects
Male, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Karyotype, Clinical Biochemistry, Lymphoproliferative disorders, Sensitivity and Specificity, Leukocyte Count, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, ComputingMilieux_MISCELLANEOUS, Aged, 030304 developmental biology, Aged, 80 and over, Automation, Laboratory, 0303 health sciences, Laboratory methods, business.industry, Biochemistry (medical), Wbc differential, Reproducibility of Results, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, General Medicine, Middle Aged, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoproliferative Disorders, 3. Good health, Tetraploidy, Leukemia, Chronic disease, 030220 oncology & carcinogenesis, Chronic Disease, Cytogenetic Analysis, Female, business
Abstract

International audience

Published
2019

29. PB1868 B-CELL PROLYMPHOCYTIC LEUKEMIA (B-PLL) AND PROLYMPHOCYTOID MANTLE CELL LYMPHOMA (PMCL) (MORE THAN 55% OF PROLYMPHOCYTES) ARE CLOSED BUT DISTINCT ENTITIES. ON BEHALF GFCH AND FILO GROUPS

Author

Frederic Davi, Caroline Algrin, Clementine Gabillaud, Nathalie Nadal, Philippe Dessen, Baptiste Gaillard, L. Baseggio, Sandra Fert-Ferrer, K. Diop, Isabelle Radford-Weiss, Marc Muller, Nathalie Auger, Benoit Quilichini, M Le Garff-Tavernier, Virginie Eclache, Evelyne Callet-Bauchu, Christine Lefebvre, Elodie Pramil, Nathalie Droin, Olivier Bernard, Damien Roos-Weil, Elise Chapiro, Stéphanie Struski, Florence Nguyen-Khac, Antoine Ittel, Catherine Settegrana, Marie-Agnès Collonge-Rame, Karim Maloum, Santos A. Susin, and Veronique Leblond

Subjects
B-cell prolymphocytic leukemia, medicine, Cancer research, Mantle cell lymphoma, Hematology, Biology, medicine.disease
Published
2019

30. An unusual case of acute leukemia

Author

Madalina Uzunov, Myrto Costopoulos, Catherine Settegrana, Amélie Trinquand, Laurence Simon, Ines Safra Zaghouani, Magali Le Garff-Tavernier, Marie Passet, Marine Armand, Elise Chapiro, Carole Fleury, Service de parasitologie - mycologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Laboratoire d'Hématologie, CHU Strasbourg, Service d'hématologie biologique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'Hématologie Clinique [CHU Pitié-Salpêtrière], Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie biologique [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Adult, Male, 030213 general clinical medicine, Myeloid, medicine.medical_treatment, T-Lymphocytes, Population, Hematopoietic stem cell transplantation, Immunophenotyping, 03 medical and health sciences, 0302 clinical medicine, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, hemic and lymphatic diseases, Medicine, Humans, Myeloid Cells, education, Chemotherapy, education.field_of_study, Acute leukemia, B-Lymphocytes, Leukemia, business.industry, flow cytometry, T-cell receptor, acute lymphoblastic T-cell leukemia, lymphoid clonality, General Medicine, Minimal residual disease, mixed phenotype acute leukemia, 3. Good health, Leukemia, Biphenotypic, Acute, medicine.anatomical_structure, Acute Disease, cytology, Cancer research, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; We report the case of a 31 year-old man diagnosed with an atypical acute leukemia difficult to characterize cytologically. The immunophenotyping identified a blastic population co-expressing myeloid, lymphoidBand lymphoid T markers suggesting the diagnosis of either a mixed phenotype acute leukemia (MPAL) or an early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Because of the poor prognosis linked to these leukemias, the patient benefited from chemotherapy targeting both myeloid and lymphoid components, followed by allogeneic hematopoietic stem cell transplantation. DNA-based techniques analyzing B and T-cell clonality identified partial rearrangements in immunoglobulin and TCR genes, allowing the monitoring of minimal residual disease. This observation highlights the difficulty to classify some atypical cases of acute leukemias. It emphasizes on the complementarity of cytomorphology, immunophenotyping by flow cytometry and molecular techniques in order to promptly characterize and treat these leukemias.

Published
2017

31. 14q deletions are associated with trisomy 12,NOTCH1mutations and unmutatedIGHVgenes in chronic lymphocytic leukemia and small lymphocytic lymphoma

Author

Boris Keren, Christine Terré, Eric Lippert, Pascaline Talmant, Sandra Fert-Ferrer, Nabila Belhouachi, Karim Maloum, Christine Lefebvre, Véronique Leblond, Catherine Settegrana, Lauren Veronese, Francine Mugneret, Marie-Agnès Collonge-Rame, Frederic Davi, Virginie Eclache, Nathalie Gachard, Florence Nguyen-Khac, Isabelle Luquet, Lucienne Michaux, Marina Lafage, Claude Lesty, Elise Chapiro, Isabelle Rafdord-Weiss, Groupe Francophone de Cytogénétique Hématologique, Catherine Helias, Nathalie Nadal, Frederik Damm, H. Merle-Beral, Hong-Anh Cung, Stéphanie Struski, Nathalie Auger, Adrien Cosson, Carole Barin, Damien Roos-Weil, and Caroline Algrin

Subjects
Cancer Research, Mutation, medicine.diagnostic_test, Chronic lymphocytic leukemia, Chromosome, Karyotype, Biology, medicine.disease, medicine.disease_cause, Leukemia, hemic and lymphatic diseases, Immunology, Genetics, Cancer research, medicine, IGHV@, Trisomy, Fluorescence in situ hybridization
Abstract

Deletions of the long arm of chromosome 14 [del(14q)] are rare but recurrently observed in mature B-cell neoplasms, particularly in chronic lymphocytic leukemia (CLL). To further characterize this aberration, we studied 81 cases with del(14q): 54 of CLL and 27 of small lymphocytic lymphoma (SLL), the largest reported series to date. Using karyotype and fluorescence in situ hybridization (FISH), the most frequent additional abnormality was trisomy 12 (tri12), observed in 28/79 (35%) cases, followed by del13q14 (12/79, 15%), delTP53 (11/80, 14%) delATM (5/79, 6%), and del6q21 (3/76, 4%). IGHV genes were unmutated in 41/53 (77%) patients, with a high frequency of IGHV1-69 (21/52, 40%). NOTCH1 gene was mutated in 14/45 (31%) patients. There was no significant difference in cytogenetic and molecular abnormalities between CLL and SLL. Investigations using FISH and SNP-array demonstrated the heterogeneous size of the 14q deletions. However, a group with the same del(14)(q24.1q32.33) was identified in 48% of cases. In this group, tri12 (P = 0.004) and NOTCH1 mutations (P = 0.02) were significantly more frequent than in the other patients. In CLL patients with del(14q), median treatment-free survival (TFS) was 27 months. In conclusion, del(14q) is associated with tri12 and with pejorative prognostic factors: unmutated IGHV genes (with over-representation of the IGHV1-69 repertoire), NOTCH1 mutations, and a short TFS.

Published
2014

32. Sex chromosome loss may represent a disease-associated clonal population in chronic lymphocytic leukemia

Author

Iléana Antony-Debré, Hong-Anh Cung, Sylvain Choquet, Nathalie Marchay, Frederic Davi, Aurore Grelier, Karim Maloum, Laurent Sutton, Madalina Uzunov, Véronique Leblond, Elise Chapiro, Christophe Parizot, Florence Nguyen-Khac, Claude Lesty, Stéphanie Mathis, Hélène Merle-Béral, and Zahia Azgui

Subjects
Cancer Research, medicine.diagnostic_test, Chronic lymphocytic leukemia, Clone (cell biology), Ficoll, Aneuploidy, Biology, medicine.disease, Peripheral blood mononuclear cell, Molecular biology, Flow cytometry, Leukemia, immune system diseases, hemic and lymphatic diseases, Immunology, Genetics, medicine, Fluorescence in situ hybridization
Abstract

Whether sex chromosome loss (SCL) is an age-related phenomenon or a cytogenetic marker of hematological disease is unclear. To address this issue in chronic lymphocytic leukemia (CLL), we investigated 20 cases with X or Y chromosome loss detected by conventional cytogenetics (CC). The frequency of SCL was low in CLL (2.3%). It was the sole abnormality, as detected by CC, in 10/20 (50%) patients. Fluorescence in situ hybridization (FISH) analyses confirmed SCL in all patients tested, present in 5-88% of cells (median: 68%). Deletions of 13q were observed by FISH in 16/20 (80%) patients. Compared with CLL without SCL, SCL was significantly associated with 13q deletion, especially when bi-allelic (P = 0.04). Co-hybridization analyses showed that SCL could be a concomitant, primary or secondary change, or be present in an independent clone. FISH analyses were performed on blood sub-populations isolated by Ficoll or flow cytometry. Comparing mononuclear cells (including CLL cells) and polynuclear cells separated by Ficoll, a maximum of 2% of polynuclear cells were found with SCL, whereas mononuclear cells exhibited a significantly higher loss frequency (range: 6-87%) (P = 0.03). Comparing B-cells (including CLL cells) and T-cells sorted by flow cytometry, the proportion of B-CD19+ cells with SCL was significantly higher (range: 88-96%) than that observed in T-CD3+ cells (range: 2-6%) (P = 0.008). We conclude that SCL has to be considered as a clonal aberration in CLL that may participate in the oncogenic process.

Published
2013

33. Chromosomal translocations involving the IGH@ locus in B-cell precursor acute lymphoblastic leukemia: 29 new cases and a review of the literature

Author

Nicole Dastugue, Carole Barin, Christian Bastard, Olivier A. Bernard, Lisa J. Russell, Stéphanie Struski, Dominique Penther, Nathalie Nadal, Peter Vandenberghe, Isabelle Tigaud, Christine Lefebvre, Elise Chapiro, Florence Nguyen-Khac, Francine Mugneret, Marie-Joelle Mozziconacci, Christine J. Harrison, Eric Lippert, Pascaline Talmant, Sylvie Taviaux, Isabelle Radford-Weiss, Serge Romana, and Hong-Anh Cung

Subjects
Adult, Male, Cancer Research, Adolescent, Chromosomal translocation, Biology, Molecular cloning, Real-Time Polymerase Chain Reaction, Translocation, Genetic, hemic and lymphatic diseases, Receptors, Erythropoietin, Genetics, medicine, Humans, Gene family, Cloning, Molecular, Child, Molecular Biology, Gene, In Situ Hybridization, Fluorescence, B cell, Aged, Aged, 80 and over, Chromosomes, Human, Pair 14, medicine.diagnostic_test, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Real-time polymerase chain reaction, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-2, Child, Preschool, CCAAT-Enhancer-Binding Proteins, Immunoglobulin heavy chain, Female, Inhibitor of Differentiation Proteins, Immunoglobulin Heavy Chains, Fluorescence in situ hybridization
Abstract

Chromosomal translocations involving the immunoglobulin heavy chain locus (IGH@) are recurrent but rare in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), and various partner genes have been described. Here, we report a new series of 29 cases of BCP-ALL with IGH@ translocations. The partner gene was identified by fluorescence in situ hybridization and/or molecular cloning in 20 patients. Members of the CEBP gene family (n = 11), BCL2 (n = 3), ID4 (n = 3), EPOR (n = 2), and TRA/D@ (n = 1) were identified and demonstrated by quantitative real-time reverse transcriptase-polymerase chain reaction to be markedly up-regulated. The present cases, added to those already reported, confirm the diversity of the partner genes, which, apart from BCL2, are specific to BCP-ALL. Collectively, patients with IGH@ translocations may represent a novel sub-group of BCP-ALL occurring in adolescents and young adults.

Published
2013

34. Cytogenetics in the management of lymphomas and lymphoproliferative disorders in adults and children: an update by the Groupe francophone de cytogénétique hématologique (GFCH)

Author

Nathalie Nadal, Christine Lefebvre, Hélène-Antoine Poirel, Evelyne Callet-Bauchu, Dominique Penther, and Elise Chapiro

Subjects
Adult, medicine.medical_specialty, Hematology, Lymphoma, Cytogenetics, Lymphoproliferative disorders, Karyotype, General Medicine, Disease, Biology, medicine.disease, Lymphoproliferative Disorders, Germline mutation, hemic and lymphatic diseases, Internal medicine, Cytogenetic Analysis, medicine, Cancer research, Humans, France, Differential diagnosis, Child, Societies, Medical
Abstract

Non-Hodgkin's lymphomas and lymphoproliferative disorders include a high number of heterogeneous entities, described in the 2008 WHO classification. This classification reflects the crucial role of a multidisciplinary approach which integrates cytogenetic results both for the notion of clonality and for differential diagnosis between these entities. The prognostic impact of some cytogenetic abnormalities or genome complexity is also confirmed for many of these entities. Novel provisional entities have been described, such as BCLU (B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma) for which karyotype is critical to distinguish BCLU from Burkitt's lymphoma. The karyotype can be established from any tumour or liquid infiltrated by lymphoma cells. Recent adaptations of technics for cellular cultures according to the subtype of known (or suspected) lymphoma have significantly improved the percentage of informative karyotypes. Conventional karyotypes remain the best technical approach recommended for most of these subtypes. Interphase and/or metaphase FISH also represents a solid and rapid approach, because of the significant number of recurrent (sometimes specific) rearrangements of these entities. Next generation sequencing technologies contribute to enrich genomic data and substantially improve the understanding of oncogenic mechanisms underlying these lymphoid malignancies. Some molecular biomarkers are already part of the diagnostic process (for example, somatic mutation of MYD88 in Waldenstrom disease) thus reinforcing the essential principle of a multidisciplinary approach for the diagnosis of all the mature lymphoid malignancies.

Published
2016

35. Chromosomal aberrations and their prognostic value in a series of 174 untreated patients with Waldenstrom's macroglobulinemia

Author

Catherine Henry, Hélène Blons, Véronique Leblondon, Dominique Penther, Virginie Eclache, Florence Nguyen-Khac, Evelyne Callet-Bauchu, Isabelle Luquet, Marie-Joelle Mozziconacci, Jean Chiesa, Sarah Mould, Aurore Grelier, Christine Terré, Stéphanie Struski, Julie Lejeune, Francine Mugneret, Sylvie Chevret, Elise Chapiro, Nathalie Gachard, Laurence Baranger, Carole Barin, Hossein Mossafa, Joris Andrieux, Lauren Veronese, Hélène Merle-Béral, Agnès Daudignon, Roger G. Owen, Jérôme Lambert, and Chrystele Bilhou-Nabera

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Karyotype, Antineoplastic Agents, Trisomy, Chromosomal translocation, Kaplan-Meier Estimate, Biology, Chromosome 18, Internal medicine, medicine, Humans, Prospective Studies, In Situ Hybridization, Fluorescence, Aged, Aged, 80 and over, Chromosome Aberrations, Chromosomes, Human, Pair 13, Chlorambucil, Chromosomes, Human, Pair 11, Macroglobulinemia, Waldenstrom macroglobulinemia, Hematology, Middle Aged, Prognosis, medicine.disease, Chromosome 4, Immunology, Chromosomes, Human, Pair 6, Female, Original Articles and Brief Reports, Chromosome Deletion, Chromosomes, Human, Pair 4, Waldenstrom Macroglobulinemia, Chromosomes, Human, Pair 18, Vidarabine, Chromosomes, Human, Pair 17, medicine.drug
Abstract

Waldenström's macroglobulinemia is a disease of mature B cells, the genetic basis of which is poorly understood. Few recurrent chromosomal abnormalities have been reported, and their prognostic value is not known. We conducted a prospective cytogenetic study of Waldenström's macroglobulinemia and examined the prognostic value of chromosomal aberrations in an international randomized trial. The main aberrations were 6q deletions (30%), trisomy 18 (15%), 13q deletions (13%), 17p (TP53) deletions (8%), trisomy 4 (8%), and 11q (ATM) deletions (7%). There was a significant association between trisomy of chromosome 4 and trisomy of chromosome 18. Translocations involving the IGH genes were rare (

Published
2012

36. LHX2 deregulation by juxtaposition with the IGH locus in a pediatric case of chronic myeloid leukemia in B-cell lymphoid blast crisis

Author

Elise Chapiro, Olivier Bernard, Florence Nguyen-Khac, Nathalie Nadal, Pascale Flandrin-Gresta, Lydia Campos, C. Vasselon, Kheira Beldjord, Sandrine Thouvenin, and Odile Fenneteau

Subjects
Regulation of gene expression, Cancer Research, Myeloid leukemia, Chromosomal translocation, Hematology, Biology, medicine.disease, Myelogenous, Leukemia, Igh locus, medicine.anatomical_structure, Oncology, medicine, Cancer research, Gene, B cell
Published
2012

37. Chronic lymphocytic leukemia and prolymphocytic leukemia with MYC translocations: a subgroup with an aggressive disease course

Author

Peter Vandenberghe, Anne Hagemeijer, Natalie Put, Virginie Eclache, Peter Konings, Lucienne Michaux, Elise Chapiro, Sophy Laibe, Carine Gervais, Christine Lefebvre, Hélène Poirel, Stéphanie Struski, Florence Nguyen-Khac, Yves Moreau, Nicole Dastugue, Iwona Wlodarska, Katrina Rack, M J Mozziconacci, Nathalie Gachard, Sandra Fert-Ferrer, Carole Barin, Katrien Van Roosbroeck, Caroline Brusselmans, Peter Meeus, Benoit Quilichini, and Isabelle Radford-Weiss

Subjects
Male, Monosomy, medicine.medical_specialty, Pathology, Chromosomes, Human, Pair 22, Chronic lymphocytic leukemia, Genes, myc, Chromosomal translocation, Biology, Translocation, Genetic, Cohort Studies, Leukemia, Prolymphocytic, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Neoplasm Invasiveness, Prolymphocytic leukemia, Aged, Retrospective Studies, Aged, 80 and over, Chromosomes, Human, Pair 14, Hematology, medicine.diagnostic_test, General Medicine, Middle Aged, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Leukemia, Case-Control Studies, Chromosomes, Human, Pair 2, Disease Progression, Cancer research, Female, CD5, Chromosomes, Human, Pair 8, Fluorescence in situ hybridization
Abstract

Translocations involving MYC are rare in chronic lymphocytic leukemia (CLL), and up to now, their prognostic significance remains unclear. We report the characteristics of 21 patients with CLL and nine patients with prolymphocytic leukemia (PLL), diagnosed in multiple centers (n = 13), which showed an MYC translocation demonstrated by fluorescence in situ hybridization. The prevalence was estimated to be

Published
2011

38. Genetic Characterization of B-Cell Prolymphocytic Leukemia (B-PLL): A Hierarchical Prognostic Model Involving MYC and TP53 Abnormalities. on Behalf of the Groupe Francophone De Cytogenetique Hematologique (GFCH) and the French Innovative Leukemia Organization (FILO) Group

Author

Sandra Fert-Ferrer, Baptiste Gaillard, Nathalie Droin, Lena Wagner, Philippe Dessen, Antoine Ittel, Evelyne Callet-Bauchu, Catherine Settegrana, Benoit Quilichini, Nathalie Auger, Virginie Eclache, Melanie Yon, Nadia Bougacha, Karim Maloum, Florence Nguyen-Khac, Elodie Pramil, Elise Chapiro, Christine Lefebvre, Clementine Gabillaud, Nathalie Nadal, Claude Lesty, Frederic Davi, Simon Bouzy, Stéphanie Struski, Damien Roos-Weil, Olivier A. Bernard, Clémentine Dillard, Thorsten Zenz, Santos A. Susin, Marie-Agnès Collonge-Rame, Magali Le Garff-Tavernier, Caroline Algrin, Sebastian Scheinost, M'Boyba Diop, Lucile Baseggio, Isabelle Radford-Weiss, Marc Muller, and Véronique Leblond

Subjects
Venetoclax, business.industry, Immunology, Chromosomal translocation, Cell Biology, Hematology, medicine.disease, Biochemistry, 03 medical and health sciences, Leukemia, chemistry.chemical_compound, 0302 clinical medicine, chemistry, 030220 oncology & carcinogenesis, Ibrutinib, B-cell prolymphocytic leukemia, Chromosome abnormality, medicine, Cancer research, Mantle cell lymphoma, Trisomy, business, 030215 immunology
Abstract

B-PLL is defined by the presence of prolymphocytes in peripheral blood exceeding 55% of lymphoid cells. The diagnosis, mainly based on clinical and morphological data, can be difficult because of overlap with other B-cell malignancies. Because of the rarity of the disease, only case reports and small series describe its cytogenetic features. Few prognostic markers have been identified in this aggressive leukemia usually resistant to standard chemo-immuno therapy. We report here the cytogenetic and molecular findings in a large series of B-PLL. We also studied the in vitro response to novel targeted drugs on primary B-PLL cells. The study included 34 cases with a diagnosis of B-PLL validated by morphological review performed by three independent expert cytologists. The diagnosis of mantle cell lymphoma was excluded by karyotype (K) and FISH using CCND1, CCND2 and CCND3 probes. Median age at diagnosis was 72 years [46-88]. K was complex (≥3 abnormalities) in 73%, and highly complex (HCK≥5) in 45%. Combining K and FISH data, the most frequent chromosomal aberrations were: translocation targeting the MYC gene [t(MYC)] (21/34, 62%), 17p deletion including TP53 gene (13/34, 38%), trisomy 18/18q (10/33, 30%), 13q14 deletion (10/34, 29%), trisomy 3 (8/33, 24%), trisomy 12 (8/34, 24%) and 8p deletion (7/31, 23%). Whole-Exome Sequencing analysis of paired tumor-control DNA was performed in 16 patients. The most frequently mutated genes were TP53(6/16, 38%), associated with del17p in all, MYD88 (n=4), BCOR (n=4), MYC (n=3), SF3B1 (n=3), FAT1 (n=3), SETD2 (n=2), CHD2 (n=2), CXCR4 (n=2), BCLAF1 (n=2) and NFASC (n=2). Distribution of the chromosomal aberrations is shown in Fig 1. The main group of patients (21/34, 62%) had a t(MYC) that was associated with a higher % of prolymphocytes (86 vs 76, p=0.03), CD38 expression (90% vs 15%,p The median overall survival (OS) for the entire cohort was 126 months with a median follow-up time of 47 months [ 0.2-141]. We found MYC activation (translocation or gain) to be associated with a shorter OS (p=0.03). Regarding MYC and del17p, we identified 3 distinct cytogenetic prognostic groups, with significant differences in OS (p=0.0006) (Fig 2). The patients without MYC activation had the lower risk (n=8, median not reached). Patients with a MYC activation without del17p had an intermediate risk (n=18, 125 months). The highest risk group corresponded to patients with both MYC and TP53 aberrations (n=7, 11 months). We performed drug response profiling on primary B-PLL cells using the ATP-based CellTiter Glo kit (Promega) (n=5). We observed that after 48h of exposure to increased doses, response was heterogeneous, with a majority of samples resistant to fludarabine (n=3), ibrutinib (n=3), idelalisib (n=4), venetoclax (n=3) and OTX015 (n=4). Annexin/PI assays using flow cytometry showed that the induced cell death could be increased by combination of ibrutinib or venetoclax with OTX015 or JQ1, two BET protein inhibitors that target MYC signaling (n=1/2). In summary, B-PLL have complex and highly complex K, a high frequency of MYC activation by translocation or gain, frequent 17p deletion, and frequent mutations in MYC, TP53, BCOR, and MYD88 genes. We identified 3 prognostic subgroups according to MYC and 17p status. Patients with MYC activation + 17p deletion have the shorter OS, and should be considered as a high-risk "double-hit" subgroup. Our results show that cytogenetic analysis is a useful diagnostic tool in B-PLL that improves prognostic stratification. We recommend to perform K and FISH (MYC and TP53) analyses systematically when a B-PLL is suspected. Our in vitro data suggest that drugs targeting the BCR and BCL2 in combination with MYC inhibition may be a therapeutic option in some patients. Disclosures Baseggio: Takeda Oncology: Honoraria.

Published
2018

39. Treatment CLL: Impact in the Dynamic of Clonal Evolution

Author

Damien Roos-Weil, Simon Bouzy, Santos A. Susin, Magali Le Garff-Tavernier, Elise Chapiro, Clementine Gabillaud, Jean Gabarre, Choquet Sylvain, Marine Armand, Anne Lavaud, Florence Nguyen-Khac, Frederic Davi, Véronique Leblond, Nadia Bougacha, Fotini Kostopoulou, Karim Maloum, Olivier Bernard, and Véronique Morel

Subjects
Cancer Research, Oncology, Evolutionary biology, business.industry, Medicine, Hematology, business, Somatic evolution in cancer
Published
2018

40. Chromosomal abnormalities in transformed Ph-negative myeloproliferative neoplasms are associated to the transformation subtype and independent of JAK2 and the TET2 mutations

Author

Joris Andrieux, Marie-Joelle Mozziconacci, Nicole Dastugue, Claude Lesty, Lucile Couronné, Olivier Kosmider, Chrystele Bilhou-Nabera, Florence Nguyen-Khac, Stéphanie Struski, Virginie Eclache, Olivier Bernard, Francine Mugneret, Dominique Penther, Marie-Agnès Collonge-Rame, Eric Lippert, Nathalie Gachard, Elise Chapiro, Christine Cabrol, Nathalie Nadal, and Marina Lafage

Subjects
Adult, Male, Cancer Research, Myeloid, DNA Mutational Analysis, Biology, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative, Dioxygenases, Young Adult, Proto-Oncogene Proteins, hemic and lymphatic diseases, Genetics, medicine, Humans, Myelofibrosis, Gene, Survival rate, Aged, Aged, 80 and over, Chromosome Aberrations, Incidence (epidemiology), Myeloid leukemia, Janus Kinase 2, Middle Aged, Prognosis, medicine.disease, Molecular biology, DNA-Binding Proteins, Survival Rate, Leukemia, Transformation (genetics), Cell Transformation, Neoplastic, medicine.anatomical_structure, Mutation, Female
Abstract

Evolution to myelofibrosis (MF), acute myeloid leukemia or myelodysplastic syndrome (AML/MDS) may occur over time in myeloproliferative neoplasms (MPN) patients most likely due to the acquisition of additional mutations. The Groupe Francophone de cytogenetique hematologique (GFCH) has collected and reviewed 82 patients with transformation of MPN (66 AML/MDS and 16 MF). JAK2V617F and TET2 mutations were searched for in 40 and 32 patients, respectively. Significantly more -7/del(7q) (P = 0.004) and -5/del(5q) (P = 0.03) were found in AML/MDS with a higher incidence of dup1q (P = 0.01) in MF. Some specific chromosomal abnormalities occurred together, for example -5/del(5q) and -17/del(17p) (P = 0.0007). In multivariate analysis, two factors were independently associated with an inferior overall survival (OS); AML/MDS transformation (P < 0.0001) and -5/del(5q) abnormality (P = 0.02). Although both giving rise to loss of 7q, der(1;7) differed from other 7q deletions in terms of distribution (lower frequency of AML/MDS, P = 0.02), association with chromosomal abnormalities (absence of -5/del(5q), P = 0.003; increased del(20q), P = 0.05), and longer OS (P = 0.0007). We detected 24/40 (60%) JAK2V617F and 8/25 (32%) TET2 mutations in samples following transformation, ranging from wild-type to mutated forms of both genes. The mutated and wild-type forms of the genes were not found to be associated with a specific chromosomal abnormality. There was no evidence that JAK2 or TET2 mutations were associated with the type of MPN transformation, whereas the type of cytogenetic abnormalities were strongly linked, perhaps indicating that they play a specific role in the transformation process.

Published
2010

41. Gain of the short arm of chromosome 2 (2p) is a frequent recurring chromosome aberration in untreated chronic lymphocytic leukemia (CLL) at advanced stages

Author

Lauren Veronese, Marc De Braekeleer, Christine Terré, Isabelle Radford-Weiss, Sylvie Taviaux, Nathalie Leporrier, Hélène Merle-Béral, Dominique Leroux, Hossein Mossafa, Florence Nguyen-Khac, Elise Chapiro, Sandra Fert-Ferrer, Evelyne Callet-Bauchu, Frederic Davi, Olivier Bernard, Laurent Sutton, Françoise Brizard, Claude Lesty, Stéphanie Struski, Christian Bastard, Isabelle Tigaud, and Sophie Raynaud

Subjects
Chromosome Aberrations, Cancer Research, Poor prognosis, Mrna expression, Advanced stage, Gene Dosage, Chromosome, Hematology, Biology, Leukemia, Lymphocytic, Chronic, B-Cell, Chromosome aberration, Molecular biology, Oncology, Chromosomes, Human, Pair 2, Cancer research, Humans, Abnormality, IGHV@, neoplasms, Untreated Chronic Lymphocytic Leukemia
Abstract

Using array-based CGH, we identified 2p gain in 22/78 (28%) untreated Binet stages B/C CLL, which was the second most frequent copy number change after 13q deletion. It never occurred as a sole abnormality and was associated with other changes (6q deletion; 1p gain). The region of 2p gain frequently included two oncogenes, REL and MYCN. All patients with gain of REL were unmutated for IGHV (p=0.03). Gain of MYCN was associated with increased mRNA expression (p=0.005), suggesting a pathogenic role for MYCN. Gain of 2p appears to be a marker of progression and may contribute to the poor prognosis.

Published
2010

42. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia

Author

Lee Machado, Lynne Minto, David S. Guttery, Lana Harder, Lisa J. Russell, Julie Irving, Heather Morrison, Takashi Akasaka, Olaf Heidenreich, Florence Nguyen-Khac, Vikki Rand, Reiner Siebert, Claire Schwab, Thiruppavaii Chandrasekaran, Melania Capasso, Holger Tönnies, Lyndal Kearney, Claudia Haferlach, Elise Chapiro, Aneela Majid, Jonathan C. Strefford, Olivier Bernard, Martin J. S. Dyer, Mike Griffiths, Anthony V. Moorman, María José Calasanz, S Gesk, Christine J. Harrison, and Inga Vater

Subjects
Adult, Adolescent, medicine.medical_treatment, Immunology, Pseudoautosomal region, Chromosomal translocation, medicine.disease_cause, Biochemistry, Cytokine Receptor Gene, Translocation, Genetic, Mice, Young Adult, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Acute lymphocytic leukemia, medicine, Animals, Humans, Lymphocytes, Receptors, Cytokine, Child, Cells, Cultured, B cell, Aged, Chromosomes, Human, Pair 14, Gene Expression Regulation, Leukemic, business.industry, Infant, Cell Biology, Hematology, Middle Aged, Embryo, Mammalian, medicine.disease, Mice, Inbred C57BL, Cell Transformation, Neoplastic, Cytokine, medicine.anatomical_structure, Child, Preschool, Cancer research, business, Carcinogenesis, Cytokine receptor, Gene Deletion
Abstract

We report 2 novel, cryptic chromosomal abnormalities in precursor B-cell acute lymphoblastic leukemia (BCP-ALL): a translocation, either t(X;14)(p22;q32) or t(Y;14)(p11;q32), in 33 patients and an interstitial deletion, either del(X)(p22.33p22.33) or del(Y)(p11.32p11.32), in 64 patients, involving the pseudoautosomal region (PAR1) of the sex chromosomes. The incidence of these abnormalities was 5% in childhood ALL (0.8% with the translocation, 4.2% with the deletion). Patients with the translocation were older (median age, 16 years), whereas the patients with the deletion were younger (median age, 4 years). The 2 abnormalities result in deregulated expression of the cytokine receptor, cytokine receptor-like factor 2, CRLF2 (also known as thymic stromal-derived lymphopoietin receptor, TSLPR). Overexpression of CRLF2 was associated with activation of the JAK-STAT pathway in cell lines and transduced primary B-cell progenitors, sustaining their proliferation and indicating a causal role of CRLF2 overexpression in lymphoid transformation. In Down syndrome (DS) ALL and 2 non-DS BCP-ALL cell lines, CRLF2 deregulation was associated with mutations of the JAK2 pseudokinase domain, suggesting oncogenic cooperation as well as highlighting a link between non-DS ALL and JAK2 mutations.

Published
2009

43. IGHV gene mutational status and LPL/ADAM29 gene expression as clinical outcome predictors in CLL patients in remission following treatment with oral fludarabine plus cyclophosphamide

Author

Olivier Tournilhac, Stéphane Leprêtre, Hélène Merle-Béral, Brigitte Dreyfus, Frederic Davi, Karim Maloum, Florence Nguyen-Khac, Beatrice Mahe, Claude Lesty, Catherine Settegrana, Bruno Cazin, Michel Leporrier, Elise Chapiro, and Alain Delmer

Subjects
Oncology, medicine.medical_specialty, Cyclophosphamide, Genes, Immunoglobulin Heavy Chain, DNA Mutational Analysis, Antineoplastic Agents, Biology, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Gene expression, Biomarkers, Tumor, medicine, Humans, Stage (cooking), Gene, Hematology, Remission Induction, General Medicine, Leukemia, Lymphocytic, Chronic, B-Cell, Minimal residual disease, 3. Good health, Fludarabine, Gene Expression Regulation, Neoplastic, ADAM Proteins, Lipoprotein Lipase, Treatment Outcome, 030220 oncology & carcinogenesis, Mutation, Immunology, IGHV@, Vidarabine, 030215 immunology, medicine.drug
Abstract

Several prognostic factors can predict the rapid progression in chronic lymphocytic leukaemia (CLL), including IGHV mutational status, cytogenetic abnormalities and, more recently, LPL/ADAM29 expression. In contrast, few studies have been devoted to the influence of these factors on clinical outcome in responding patients after therapy. We here propose to analyse the impact of IGHV gene status, LPL and ADAM29 gene expression on disease-free survival (DFS) and overall survival (OS) in 41 stage B or C CLL patients in remission after oral fludarabine plus cyclophosphamide. The median follow-up was of 64 (16-74) months. Sequencing of IGHV showed mutated (M) VH genes in 16 of 41 cases and unmutated (UM) in 25 cases. Analysis of LPL and ADAM29 expression in 35 of 41 cases showed overexpression of ADAM29 in 17 cases (14 M and three UM) and LPL in 18 cases (all UM). Patients expressing UM IGHV and LPL had shorter DFS and OS when compared to patients expressing M IGHV and/or ADAM29. Furthermore, blood minimal residual disease (MRD) evaluation using four-colour flow cytometry was performed in 33 out the 41 patients. We showed that patients who achieved phenotypic remission displayed longer DFS than those with MRD(+). Our results support the use of LPL and ADAM29 gene expression associated to IGHV mutational status for predicting the clinical outcome of patients treated by oral fludarabine + cyclophosphamide and could be considered for treatment strategies.

Published
2009

44. The most frequent t(14;19)(q32;q13)-positive B-cell malignancy corresponds to an aggressive subgroup of atypical chronic lymphocytic leukemia

Author

Isabelle Radford-Weiss, Olivier Bernard, Carole Barin, Sophie Raynaud, M J Mozziconacci, Roland Berger, Sylvie Ramond, Florence Nguyen-Khac, Dominique Leroux, Francine Mugneret, H. Merle-Beral, Joris Andrieux, Eric Lippert, Pascaline Talmant, Stéphanie Struski, Françoise Berger, Christine Lefebvre, Christian Bastard, Frederic Davi, Christine Terré, Martine Jotterand, Pascale Felman, Hossein Mossafa, Evelyne Callet-Bauchu, Isabelle Luquet, and Elise Chapiro

Subjects
Adult, Male, Cancer Research, Pathology, medicine.medical_specialty, Chronic lymphocytic leukemia, Biology, Malignancy, Translocation, Genetic, Immunophenotyping, B-Cell Lymphoma 3 Protein, Proto-Oncogene Proteins, hemic and lymphatic diseases, Leukemia, B-Cell, medicine, Humans, B cell malignancy, Aged, Aged, 80 and over, Chromosomes, Human, Pair 14, NF-kappa B, Hematology, Middle Aged, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Oncology, Female, Chromosomes, Human, Pair 19, Transcription Factors
Abstract

The most frequent t(14;19)(q32;q13)-positive B-cell malignancy corresponds to an aggressive subgroup of atypical chronic lymphocytic leukemia

Published
2008

45. CD47 agonist peptides induce programmed cell death in refractory chronic lymphocytic leukemia B cells via PLCγ1 activation: evidence from mice and humans

Author

Hélène Merle-Béral, Marika Sarfati, Frederic Davi, Philippe Karoyan, Magali Le Garff-Tavernier, Santos A. Susin, Héloise Boullet, Elise Chapiro, Tarik Attout, Sandrine Barbier, Ana Carolina Martínez-Torres, Florence Nguyen-Khac, Roba Moumné, Danielle Chateau, Linda Herbi, Pierre Launay, Claire Quiney, Laura Vela, HAL UPMC, Gestionnaire, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'hématologie biologique [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de recherche sur l'Inflammation ( CRI ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Service d'hématologie biologique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], and Centre de recherche du Centre Hospitalier de l'Université de Montréal ( CRCHUM )

Subjects
Agonist, Male, medicine.drug_class, Chronic lymphocytic leukemia, Lymphocyte, Apoptosis, CD47 Antigen, Biology, Thrombospondin 1, Mice, Immune system, Mice, Inbred NOD, immune system diseases, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, hemic and lymphatic diseases, medicine, Animals, Humans, Aged, Aged, 80 and over, B-Lymphocytes, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Phospholipase C gamma, CD47, General Medicine, Middle Aged, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Leukemia, medicine.anatomical_structure, Drug Resistance, Neoplasm, Immunology, Medicine, Female, Refractory Chronic Lymphocytic Leukemia, CD5, Peptides, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract

Background Chronic lymphocytic leukemia (CLL), the most common adulthood leukemia, is characterized by the accumulation of abnormal CD5+ B lymphocytes, which results in a progressive failure of the immune system. Despite intense research efforts, drug resistance remains a major cause of treatment failure in CLL, particularly in patients with dysfunctional TP53. The objective of our work was to identify potential approaches that might overcome CLL drug refractoriness by examining the pro-apoptotic potential of targeting the cell surface receptor CD47 with serum-stable agonist peptides. Methods and Findings In peripheral blood samples collected from 80 patients with CLL with positive and adverse prognostic features, we performed in vitro genetic and molecular analyses that demonstrate that the targeting of CD47 with peptides derived from the C-terminal domain of thrombospondin-1 efficiently kills the malignant CLL B cells, including those from high-risk individuals with a dysfunctional TP53 gene, while sparing the normal T and B lymphocytes from the CLL patients. Further studies reveal that the differential response of normal B lymphocytes, collected from 20 healthy donors, and leukemic B cells to CD47 peptide targeting results from the sustained activation in CLL B cells of phospholipase C gamma-1 (PLCγ1), a protein that is significantly over-expressed in CLL. Once phosphorylated at tyrosine 783, PLCγ1 enables a Ca2+-mediated, caspase-independent programmed cell death (PCD) pathway that is not down-modulated by the lymphocyte microenvironment. Accordingly, down-regulation of PLCγ1 or pharmacological inhibition of PLCγ1 phosphorylation abolishes CD47-mediated killing. Additionally, in a CLL-xenograft model developed in NOD/scid gamma mice, we demonstrate that the injection of CD47 agonist peptides reduces tumor burden without inducing anemia or toxicity in blood, liver, or kidney. The limitations of our study are mainly linked to the affinity of the peptides targeting CD47, which might be improved to reach the standard requirements in drug development, and the lack of a CLL animal model that fully mimics the human disease. Conclusions Our work provides substantial progress in (i) the development of serum-stable CD47 agonist peptides that are highly effective at inducing PCD in CLL, (ii) the understanding of the molecular events regulating a novel PCD pathway that overcomes CLL apoptotic avoidance, (iii) the identification of PLCγ1 as an over-expressed protein in CLL B cells, and (iv) the description of a novel peptide-based strategy against CLL., In this study, Santos Susin and colleagues demonstrate that a serum-stable CD47 agonist peptide is highly effective at inducing apoptosis in chronic lymphocytic leukemia B-cells and mice., Editors’ Summary Background Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia (cancer of the white blood cells). It accounts for about a third of all adult leukemias, and about one in 200 people will develop CLL during their lifetime, usually in old age. White blood cells (including T and B lymphocytes) are made by the bone marrow (the soft center of certain bones in the body) and help the body fight infections. Leukemia begins when a bone marrow cell acquires genetic changes (mutations and chromosomal abnormalities) that make it grow and develop abnormally. Over time, the abnormal cells accumulate in the bone marrow, blood, and lymphoid organs (lymph nodes and spleen) (malignant B lymphocytes accumulate in the case of CLL) and stop the marrow producing healthy blood cells. CLL does not usually cause any symptoms during its early stages and is often diagnosed as a result of a routine blood test. Some patients, however, develop painless swellings in the lymph nodes in the neck, armpit, or groin. Other symptoms of CLL include tiredness, frequent infections, and weight loss. Treatments for CLL, which are not given unless symptoms develop, include chemotherapy, immunotherapy, and targeted therapies, which attack cancer cells without harming normal cells. Why Was This Study Done? CLL develops very slowly, and people with CLL usually live for many years after their diagnosis. However, there is no cure for CLL, and treatment fails in up to a quarter of patients because resistance to chemotherapy develops. The outlook (prognosis) is particularly bad for patients whose cancer cells contain a dysfunctional TP53 gene (TP53 encodes a protein that normally regulates cell division and cell death). Although some new therapies have recently been approved in the US and Europe, additional approaches to the treatment of CLL are still needed. One potential target for new treatments is the cell surface receptor CD47. In CLL cells, activation of CD47 by a small fragment (peptide) of thrombospondin-1 (a protein that binds to CD47) called 4N1K rapidly induces caspase-independent programmed cell death (PCD), a type of cell death in which the cell uses specialized cellular machinery to kill itself. (PCD normally controls cell numbers and eliminates cells that threaten an animal’s survival, but cancer cells often resist PCD.) Unfortunately, peptides are usually degraded quickly in the human body, which limits their usefulness as therapeutic agents. Here, therefore, the researchers investigate whether PKHB1, a variant of 4N1K designed to be stable in the body (a “serum-stable” agonist peptide), might provide a new approach to the treatment of CLL. What Did the Researchers Do and Find? The researchers tested the ability of PKHB1 to kill malignant CLL B lymphocytes grown from blood samples collected from 80 patients with CLL. PKHB1 efficiently killed these cells, including those from individuals with a dysfunctional TP53 gene but, importantly, did not kill either normal T and B lymphocytes collected from healthy donors or the residual normal T and B lymphocytes present in the patient samples. Genetic and molecular analyses undertaken by the researchers indicated that the differential response of normal and leukemic B lymphocytes to PKHB1 was the result of sustained activation of a protein called phospholipase C gamma-1 (PLCγ1) in the malignant CLL B lymphocytes. Other experiments showed that PLCγ1 activation drove the induction of a new PCD pathway (a calcium-mediated, caspase-independent pathway) that was not down-regulated by survival stimuli provided by the lymphocyte microenvironment. Finally, the researchers report that injection of PKHB1 reduced the tumor burden in a mouse model of CLL. What Do These Findings Mean? Taken together, these findings suggest that serum-stable CD47 agonist peptides represent a potential new treatment for CLL that could circumvent the problem of chemotherapy resistance and eliminate malignant CLL B lymphocytes while sparing residual normal B and T lymphocytes. These findings also demonstrate that PKHB1, the serum-stable CD47 agonist peptide tested in this study, directly induces a novel PCD pathway, thereby overcoming the innate avoidance of apoptosis by CLL cells. Before peptide-based strategies for the treatment of CLL can enter clinical trials, however, further studies are needed to develop peptides with increased stability and increased ability to bind to and activate CD47. Moreover, because the mouse CLL model used here incompletely recreates the development of CLL in people, the effectiveness and safety of this pioneer approach needs to be tested much more rigorously in animals before any clinical trials are initiated. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001796. The US National Cancer Institute provides information about cancer and how it develops, about targeted cancer therapies, and about CLL and its treatment (in English and Spanish) Cancer Research UK, a not-for-profit organization, provides general information about cancer and how it develops and detailed information about CLL The UK National Health Service website also provides information about CLL The American Society for Hematology provides general information about blood cancer and detailed information about leukemia, including CLL The French Society for Hematology provides general information about CLL (in French) The not-for-profit Force Hemato organization provides general information about lymphoproliferative disorders and resources for patients and families (in French) The not-for-profit organization HealthTalkOnline provides personal stories about living with CLL Wikipedia provides information about programmed cell death and about CD47 (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)

Published
2015

46. Overexpression of CEBPA resulting from the translocation t(14;19)(q32;q13) of human precursor B acute lymphoblastic leukemia

Author

Florence Nguyen-Khac, Stéphanie Struski, Roland Berger, Olivier Bernard, Carole Barin, Sandra Fert-Ferrer, Jonathan C. Strefford, Isabelle Radford-Weiss, Michel Lessard, Odile Maarek, Christine J. Harrison, Christian Bastard, Elise Chapiro, Lisa J. Russell, Véronique Della-Valle, and Hélène Cavé

Subjects
Adult, Male, Immunoglobulin gene, Myeloid, Immunology, Biology, medicine.disease_cause, Biochemistry, Translocation, Genetic, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, hemic and lymphatic diseases, Acute lymphocytic leukemia, CEBPA, medicine, Humans, RNA, Neoplasm, Child, Aged, Chromosomes, Human, Pair 14, Gene Rearrangement, Genes, Immunoglobulin, Myeloid leukemia, Cell Biology, Hematology, Gene rearrangement, Middle Aged, medicine.disease, Molecular biology, Gene Expression Regulation, Neoplastic, Haematopoiesis, medicine.anatomical_structure, CCAAT-Enhancer-Binding Proteins, Cancer research, Female, Immunoglobulin Heavy Chains, Carcinogenesis, Chromosomes, Human, Pair 19
Abstract

Subtle variation in the expression or function of a small group of transcription factors can drive leukemogenesis. The CEBPA protein is known to regulate the balance between cell proliferation and differentiation during early hematopoietic development and myeloid differentiation. In human myeloid leukemia, CEBPA is frequently inactivated by mutation and indirect and posttranslational mechanisms, in keeping with tumor suppressor properties. We report that CEBPA is activated by juxtaposition to the immunoglobulin gene enhancer upon its rearrangement with the immunoglobulin heavy-chain locus in precursor B-cell acute lymphoblastic leukemia harboring t(14;19)(q32;q13). Overexpression of apparently normal CEBPA RNA or protein was observed in 6 patients. These data indicate that CEBPA may exhibit oncogenic as well as tumor suppressor properties in human leukemogenesis.

Published
2006

47. Expression of T-lineage-affiliated transcripts and TCR rearrangements in acute promyelocytic leukemia: implications for the cellular target of t(15;17)

Author

David Grimwade, Frederic Davi, E. Nugent, Elizabeth Macintyre, Kheira Beldjord, Corinne Millien, Elise Chapiro, Vahid Asnafi, Torsten Haferlach, and Eric Delabesse

Subjects
Acute promyelocytic leukemia, Myeloid, T-Lymphocytes, CD3, Immunology, Biology, Gene Rearrangement, T-Lymphocyte, Biochemistry, Translocation, Genetic, Cohort Studies, Leukemia, Promyelocytic, Acute, medicine, Humans, Cell Lineage, RNA, Messenger, Lymphopoiesis, Chromosomes, Human, Pair 15, Gene Expression Regulation, Leukemic, Gene Expression Profiling, Myeloid leukemia, Cell Biology, Hematology, Gene rearrangement, medicine.disease, Leukemia, Cell Transformation, Neoplastic, medicine.anatomical_structure, Terminal deoxynucleotidyl transferase, biology.protein, Chromosomes, Human, Pair 17, Transcription Factors
Abstract

Acute promyelocytic leukemia (APL) is the most differentiated form of acute myeloid leukemia (AML) and has generally been considered to result from transformation of a committed myeloid progenitor. Paradoxically, APL has long been known to express the T-cell lymphoid marker, CD2. We searched for other parameters indicative of T-cell lymphoid specification in a cohort of 36 APL cases, revealing a frequent but asynchronous T-cell lymphoid program most marked in the hypogranular variant (M3v) subtype, with expression of PTCRA, sterile TCRA, and TCRG transcripts and TCRG rearrangement in association with sporadic cytoplasmic expression of CD3 or TdT proteins. Gene-expression profiling identified differentially expressed transcription factors that have been implicated in lymphopoiesis. These data carry implications for the hematopoietic progenitor targeted by the PML-RARA oncoprotein in APL and are suggestive of a different cellular origin for classic hypergranular (M3) and variant forms of the disease. They are also consistent with the existence and subsequent transformation of progenitor populations with lymphoid/myeloid potential.

Published
2006

49. [Chronic myeloid leukemia with variant e19a2 BCR-ABL1 fusion transcript: interest of the molecular identification at diagnosis for minimal residual disease follow-up]

Author

Nabila Belhouachi, Hélène Merle-Béral, Jean-Michel Cayuela, Florence Nguyen-Khac, Karim Maloum, Elise Chapiro, Nicolas Gendron, Frederic Davi, Véronique Morel, and Zahia Azgui

Subjects
Oncology, medicine.medical_specialty, Neoplasm, Residual, Chromosomes, Human, Pair 22, Fusion Proteins, bcr-abl, Antineoplastic Agents, Disease, Translocation, Genetic, hemic and lymphatic diseases, Internal medicine, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, medicine, Humans, Aged, business.industry, Remission Induction, Myeloid leukemia, Genetic Variation, Imatinib, General Medicine, Protein-Tyrosine Kinases, Minimal residual disease, Real-time polymerase chain reaction, Imatinib mesylate, Pyrimidines, Nilotinib, Fusion transcript, Imatinib Mesylate, Female, business, Chromosomes, Human, Pair 9, medicine.drug, Follow-Up Studies
Abstract

We report here the case of a sixty-eight-year old woman with chronic myeloid leukemia. Molecular techniques identified the presence of the rare e19a2 BCR-ABL1 transcript. The patient was treated by 1(st) generation tyrosine-kinase inhibitor (TKI) (imatinib). Disease monitoring was performed by cytogenetic analyses and quantification of the BCR-ABL1 transcript. After 3 months, the treatment was modified due to an absence of biological response and poor tolerance. After 21 months with 2nd generation TKIs (nilotinib), the patient was responding optimally to treatment, with a complete cytogenetic response and a major molecular response. This observation emphasizes the importance of determining the chromosomal breakpoints at diagnosis to enable adequate molecular monitoring of residual disease. Careful monitoring of minimal residual disease is important to thoroughly assess the response to treatment, detect resistance and adapt the therapeutic strategy. The kinetics and the depth of the response to TKI also represent major prognostic factors. Molecular monitoring is performed using real-time quantitative PCR, which has to be adapted to each type of transcript. For rare BCR-ABL1 transcripts, an international standardization, as it is developed for conventional transcripts, is lacking. Yet, such a harmonization would be useful to assess in an optimal and large scale way the response to TKI in these patients, and to determine what the best management is.

Published
2014

50. A new human mast cell line expressing a functional IgE receptor converts to tumorigenic growth by KIT D816V transfection

Author

Harald Herrmann, Rosine Saleh, Emir Hadzijusufovic, Hélène Merle-Béral, Magali Legarff-Tavernier, Peter Valent, Frédéric Subra, Michel Arock, Florence Nguyen-Khac, Patrice Dubreuil, Katharina Blatt, Catherine Blanc, Sabine Cerny-Reiterer, Michael Willmann, Elise Chapiro, Vanessa Desplat, Siham Bibi, Thomas Rülicke, Ghaith Wedeh, Patrick Bonnemye, Sylvie Jeanningros, Irina Sadovnik, Angewandte Physik, Universität Paderborn (UPB), Medizinische Universität Wien = Medical University of Vienna, Service d'hématologie biologique [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Division of Hematology/Hemostaseology, Medical University Vienna, Ludwig Boltzmann Cluster Oncology, Fondation de France, Austrian Science Fund (FWF), SFB project [F4611, F4704-B20], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Paderborn ( UPB ), Service d'hématologie biologique, CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE)

Subjects
Immunology, Blotting, Western, Stem cell factor, Context (language use), Cell Separation, Mice, SCID, Immunoglobulin E, Transfection, Biochemistry, Proinflammatory cytokine, Cell Line, Mice, Mastocytosis, Systemic, Mice, Inbred NOD, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Animals, Humans, Mast Cells, Systemic mastocytosis, Mice, Knockout, biology, Cell Biology, Hematology, medicine.disease, Mast cell, Flow Cytometry, Molecular biology, 3. Good health, Proto-Oncogene Proteins c-kit, medicine.anatomical_structure, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], biology.protein, Mast cell sarcoma, Heterografts
Abstract

International audience; In systemic mastocytosis (SM), clinical problems arise from factor-independent proliferation of mast cells (MCs) and the increased release of mediators by MCs, but no human cell line model for studying MC activation in the context of SM is available. We have created a stable stem cell factor (SCF)-dependent human MC line, ROSA(KIT WT), expressing a fully functional immunoglobulin E (IgE) receptor. Transfection with KIT D816V converted ROSA(KIT WT) cells into an SCF-independent clone, ROSA(KIT D816V), which produced a mastocytosis-like disease in NSG mice. Although several signaling pathways were activated, ROSA(KIT D816V) did not exhibit an increased, but did exhibit a decreased responsiveness to IgE-dependent stimuli. Moreover, NSG mice bearing ROSA(KIT D816V)-derived tumors did not show mediator-related symptoms, and KIT D816V-positive MCs obtained from patients with SM did not show increased IgE-dependent histamine release or CD63 upregulation. Our data show that KIT D816V is a disease-propagating oncoprotein, but it does not activate MCs to release proinflammatory mediators, which may explain why mediator-related symptoms in SM occur preferentially in the context of a coexisting allergy. ROSA(KIT D816V) may provide a valuable tool for studying the pathogenesis of mastocytosis and should facilitate the development of novel drugs for treating SM patients.

Published
2014

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