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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. Inflammation is predictive of outcome in Waldenström macroglobulinemia treated by Bruton tyrosine kinase inhibitors: a multicentric real-life study

Author

Pierre-Edouard Debureaux, Nathalie Forgeard, Dikelele Elessa, Stéphanie Harel, Laurent Frenzel, Bruno Royer, Alexis Talbot, Sylvain Choquet, Frederic Davi, Florence Nguyen-Khac, Wendy Cuccuini, Morgane Cheminant, Clotilde Bravetti, Gregory Lazarian, Sophie Kaltenbach, Olivier Hermine, Damien Roos-Weil, Marion Espéli, Karl Balabanian, and Bertrand Arnulf

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2023
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3. 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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4. 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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5. Mast cell density and its clinical relevance in Waldenström's macroglobulinemia

Author

Richard Lemal, Stéphanie Poulain, Albane Ledoux‐Pilon, Lauren Veronese, Andrei Tchirkov, Benjamin Lebecque, Thomas Tassin, Jacques‐Olivier Bay, Frédéric Charlotte, Florence Nguyen‐Khac, Marc Berger, Catherine Godfraind, Loïc Ysebaert, Frédéric Davi, Bruno Pereira, Véronique Leblond, Olivier Hermine, Romain Guièze, Franck Pagès, and Olivier Tournilhac

Subjects
mast cells, tumor biology, Waldenström's macroglobulinemia, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Abstract The presence of numerous mast cells (MCs) mixed with tumor cells in the bone marrow (BM) is a hallmark of the diagnosis of Waldenström's macroglobulinemia (WM). MCs have been shown to support lymphoplasmacytic cell growth, but there is thus far no demonstration of the prognostic impact of BM MC density in WM. We investigated BM MC density by sensitive and specific digital quantification, allowing the analysis of a large area infiltrated by BM tumor cells. A total of 65 WM patients were investigated, including 54 at diagnosis and 11 at relapse. Tryptase and CD20 immunohistochemisty staining was performed on contiguous sections of deparaffinized BM trephine biopsies. After numerization of each section, the BM surface area was manually marked out, excluding the bone framework and adipocytes to limit the analyses to only hematopoietic tissue. MCs were assessed using a digital tool previously used to quantify immune‐cell infiltrates on tumor‐tissue sections. Deep next‐generation sequencing and allele‐specific PCR were used to explore the MYD88 and CXCR4 mutational status. MC density was heterogeneous among the WM patients. An optimal MC density threshold (> 56 MC.mm–2) was defined according to ROC curve analysis of overall survival. A higher MC density (> 56 MC.mm–2) was associated with greater BM involvement by WM lymphoplasmacytic cells and less hepatosplenic involvement (p = 0.023). Furthermore, MC density significantly correlated with a higher ISSWM score (p = 0.0003) in symptomatic patients. Patients with a higher MC density showed shorter median OS (56.5 months vs. nonreached, p = 0.0004), even in multivariate analysis after controlling for other predictive variables, such as age, ISSWM score, and CXCR4 mutational status. In conclusion, MC density can be accurately measured in WM patients using a specific digital tool on well‐outlined hematopoietic tissue surfaces. High MC density is associated with aggressive features and a poor clinical outcome, emphasizing the need for further investigation of the involvement of MCs in the pathophysiology of WM.

Published
2022
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6. 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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7. 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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8. 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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9. Therapy-related Myeloid Neoplasms in Patients With Chronic Lymphocytic Leukemia Who Received FCR/FC as Frontline Therapy

Author

Kamel Laribi, Alix Baugier de Materre, David Ghez, Caroline Dartigeas, Cécile Tomowiak, Béatrice Mahé, Jean-Baptiste Micol, Fatiha Merabet, Stéphane Leprêtre, Charles Herbaux, Loïc Ysebaert, Ronan Le Calloch, Lise Willems, Maud Voldoire, Damien Roos-Weil, Clotilde Bravetti, Yamina Touileb, Frédéric Davi, Florence Nguyen-Khac, Karim Maloum, and Marie C. Béné

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2022
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10. Ascorbic acid (vitamin C) synergistically enhances the therapeutic effect of targeted therapy in chronic lymphocytic leukemia

Author

Walaa Darwiche, Cathy Gomila, Hakim Ouled-Haddou, Marie Naudot, Cécile Doualle, Pierre Morel, Florence Nguyen-Khac, Loïc Garçon, Jean-Pierre Marolleau, and Hussein Ghamlouch

Subjects
Chronic lymphocytic leukemia, Ascorbic acid, Vitamin C, Cytotoxicity, Drug combination, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Novel, less toxic, cost-effective and safe therapeutic strategies are needed to improve treatment of chronic lymphocytic leukemia (CLL). Ascorbic acid (AA, vitamin C) has shown a potential anti-cancer therapeutic activity in several cancers. However, the anti-cancer effects of ascorbic acid on CLL B-cells have not been extensively studied. We aimed in this study to evaluate the in vitro therapeutic activity using clinically relevant conditions. Methods Primary CLL B-cells and two CLL cell lines were exposed to a dose that is clinically achievable by AA oral administration (250 μM), and cell death and potential mechanisms were assessed. The role of the protective CLL microenvironment was studied. Synergistic interaction between AA and CLL approved drugs (Ibrutinib, Idelalisib and Venetoclax) was also evaluated. Results Ascorbic acid is cytotoxic for CLL B-cells at low dose (250 μM) but spares healthy B-cells. Ascorbic-acid-induced cytotoxicity involved pro-oxidant damage through the generation of reactive oxygen species in the extracellular media and in CLL cells, and induced caspase-dependent apoptosis. We also found that AA treatment overcame the supportive survival effect provided by microenvironment including bone marrow mesenchymal stem cells, T-cell cues (CD40L + IL-4), cytokines and hypoxia. Our data suggest that resistance to AA could be mediated by the expression of the enzyme catalase in some CLL samples and by the glucose metabolite pyruvate. We also demonstrated that AA synergistically potentiates the cytotoxicity of targeted therapies used in or being developed for CLL. Conclusion These preclinical results point to AA as an adjuvant therapy with potential to further improve CLL treatments in combination with targeted therapies.

Published
2020
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11. 'Double-Hit' Chronic Lymphocytic Leukemia, Involving the TP53 and MYC Genes

Author

Florence Nguyen-Khac

Subjects
TP53, MYC, 17p deletion, chronic lymphocytic leukemia, MYC gain, MYC translocation, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Although the 17p deletion [del(17p)] is rare in cases of treatment-naive chronic lymphocytic leukemia (CLL), its frequency is higher in refractory/relapsed CLL – particularly in patients undergoing chemo(immuno)therapy. TP53 disruption (deletion and/or mutation) is the strongest prognostic factor for refractoriness to chemotherapy; the use of Bruton tyrosine kinase inhibitors and BCL2 inhibitors is then indicated. Rare cases of CLL can also harbor translocation or gain of the MYC oncogene. “Double-hit CLL” (with del(17p) and MYC gain) is associated with a very poor prognosis. The prognostic impact of TP53 disruption with MYC aberrations in patients receiving targeted therapies must now be evaluated.

Published
2022
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12. 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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13. 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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14. Keeping Cell Death Alive: An Introduction into the French Cell Death Research Network

Author

Gabriel Ichim, Benjamin Gibert, Sahil Adriouch, Catherine Brenner, Nathalie Davoust, Solange Desagher, David Devos, Svetlana Dokudovskaya, Laurence Dubrez, Jérôme Estaquier, Germain Gillet, Isabelle Guénal, Philippe P. Juin, Guido Kroemer, Patrick Legembre, Romain Levayer, Stéphen Manon, Patrick Mehlen, Olivier Meurette, Olivier Micheau, Bernard Mignotte, Florence Nguyen-Khac, Nikolay Popgeorgiev, Jean-Luc Poyet, Muriel Priault, Jean-Ehrland Ricci, Franck B. Riquet, Santos A. Susin, Magali Suzanne, Pierre Vacher, Ludivine Walter, and Bertrand Mollereau

Subjects
cell death, apoptosis, necrosis, cancer, Microbiology, QR1-502
Abstract

Since the Nobel Prize award more than twenty years ago for discovering the core apoptotic pathway in C. elegans, apoptosis and various other forms of regulated cell death have been thoroughly characterized by researchers around the world. Although many aspects of regulated cell death still remain to be elucidated in specific cell subtypes and disease conditions, many predicted that research into cell death was inexorably reaching a plateau. However, this was not the case since the last decade saw a multitude of cell death modalities being described, while harnessing their therapeutic potential reached clinical use in certain cases. In line with keeping research into cell death alive, francophone researchers from several institutions in France and Belgium established the French Cell Death Research Network (FCDRN). The research conducted by FCDRN is at the leading edge of emerging topics such as non-apoptotic functions of apoptotic effectors, paracrine effects of cell death, novel canonical and non-canonical mechanisms to induce apoptosis in cell death-resistant cancer cells or regulated forms of necrosis and the associated immunogenic response. Collectively, these various lines of research all emerged from the study of apoptosis and in the next few years will increase the mechanistic knowledge into regulated cell death and how to harness it for therapy.

Published
2022
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16. Chromosome banding analysis and genomic microarrays are both useful but not equivalent methods for genomic complexity risk stratification in chronic lymphocytic leukemia patients

Author

Silvia Ramos-Campoy, Anna Puiggros, Sílvia Beà, Sandrine Bougeon, María José Larráyoz, Dolors Costa, Helen Parker, Gian Matteo Rigolin, Margarita Ortega, María Laura Blanco, Rosa Collado, Rocío Salgado, Tycho Baumann, Eva Gimeno, Carolina Moreno, Francesc Bosch, Xavier Calvo, María José Calasanz, Antonio Cuneo, Jonathan C. Strefford, Florence Nguyen-Khac, David Oscier, Claudia Haferlach, Jacqueline Schoumans, and Blanca Espinet

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

Genome complexity has been associated with poor outcome in patients with chronic lymphocytic leukemia (CLL). Previous cooperative studies established five abnormalities as the cut-off that best predicts an adverse evolution by chromosome banding analysis (CBA) and genomic microarrays (GM). However, data comparing risk stratification by both methods are scarce. Herein, we assessed a cohort of 340 untreated CLL patients highly enriched in cases with complex karyotype (CK) (46.5%) with parallel CBA and GM studies. Abnormalities found by both techniques were compared. Prognostic stratification in three risk groups based on genomic complexity (0-2, 3- 4 and ≥5 abnormalities) was also analyzed. No significant differences in the percentage of patients in each group were detected, but only a moderate agreement was observed between methods when focusing on individual cases (κ=0.507; P

Published
2021
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17. Diagnosis and Treatment of Chronic Lymphocytic Leukemia: Recommendations of the French CLL Study Group (FILO)

Author

Anne Quinquenel, Thérèse Aurran-Schleinitz, Aline Clavert, Florence Cymbalista, Caroline Dartigeas, Frédéric Davi, Sophie de Guibert, Alain Delmer, Marie-Sarah Dilhuydy, Pierre Feugier, Luc-Matthieu Fornecker, David Ghez, Romain Guieze, Kamel Laribi, Véronique Leblond, Stéphane Leprêtre, Rémi Letestu, Vincent Lévy, Florence Nguyen-Khac, Anne-Sophie Michallet, Cécile Tomowiak, Olivier Tournilhac, Loïc Ysebaert, Xavier Troussard, and on the behalf of the FILO-LLC Group

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

Abstract. As a result of significant recent developments, the management of patients with chronic lymphocytic leukemia (CLL) is changing, and new therapeutic options will continue to emerge in the near future. The recommendations of the French Innovative Leukemia Organization (FILO-CLL) group presented here are intended to provide practical recommendations for physicians taking care of CLL patients, taking into account the availability of both biological tests and therapies in daily practice in France at the time of publication. This text details the documented information and guidelines on diagnosis, indications for treatment, infectious complications and therapeutic strategies in frontline and relapsed CLL as well as in particular conditions such as autoimmune cytopenia or Richter syndrome.

Published
2020
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18. Genomic arrays identify high-risk chronic lymphocytic leukemia with genomic complexity: a multi-center study

Author

Alexander C. Leeksma, Panagiotis Baliakas, Theodoros Moysiadis, Anna Puiggros, Karla Plevova, Anne-Marie van der Kevie-Kersemaekers, Hidde Posthuma, Ana E. Rodriguez-Vicente, Anh Nhi Tran, Gisela Barbany, Larry Mansouri, Rebeqa Gunnarsson, Helen Parker, Eva van den Berg, Mar Bellido, Zadie Davis, Meaghan Wall, Ilaria Scarpelli, Anders Österborg, Lotta Hansson, Marie Jarosova, Paolo Ghia, Pino Poddighe, Blanca Espinet, Sarka Pospisilova, Constantine Tam, Loïc Ysebaert, Florence Nguyen-Khac, David Oscier, Claudia Haferlach, Jacqueline Schoumans, Marian Stevens-Kroef, Eric Eldering, Kostas Stamatopoulos, Richard Rosenquist, Jonathan C. Strefford, Clemens Mellink, and Arnon P. Kater

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

Complex karyotype (CK) identified by chromosome-banding analysis (CBA) has shown prognostic value in chronic lymphocytic leukemia (CLL). Genomic arrays offer high-resolution genome-wide detection of copy-number alterations (CNAs) and could therefore be well equipped to detect the presence of a CK. Current knowledge on genomic arrays in CLL is based on outcomes of single center studies, in which different cutoffs for CNA calling were used. To further determine the clinical utility of genomic arrays for CNA assessment in CLL diagnostics, we retrospectively analyzed 2293 arrays from 13 diagnostic laboratories according to established standards. CNAs were found outside regions captured by CLL FISH probes in 34% of patients, and several of them including gains of 8q, deletions of 9p and 18p (p

Published
2020
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19. 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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20. Activation of Interferon Signaling in Chronic Lymphocytic Leukemia Cells Contributes to Apoptosis Resistance via a JAK-Src/STAT3/Mcl-1 Signaling Pathway

Author

Brigitte Bauvois, Elodie Pramil, Ludovic Jondreville, Claire Quiney, Florence Nguyen-Khac, and Santos A. Susin

Subjects
apoptosis, CLL, IFN signaling, Mcl-1, STAT3, survival, Biology (General), QH301-705.5
Abstract

Besides their antiviral and immunomodulatory functions, type I (α/β) and II (γ) interferons (IFNs) exhibit either beneficial or detrimental effects on tumor progression. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of abnormal CD5+ B lymphocytes that escape death. Drug resistance and disease relapse still occur in CLL. The triggering of IFN receptors is believed to be involved in the survival of CLL cells, but the underlying molecular mechanisms are not yet characterized. We show here that both type I and II IFNs promote the survival of primary CLL cells by counteracting the mitochondrial (intrinsic) apoptosis pathway. The survival process was associated with the upregulation of signal transducer and activator of transcription-3 (STAT3) and its target anti-apoptotic Mcl-1. Furthermore, the blockade of the STAT3/Mcl-1 pathway by pharmacological inhibitors against STAT3, TYK2 (for type I IFN) or JAK2 (for type II IFN) markedly reduced IFN-mediated CLL cell survival. Similarly, the selective Src family kinase inhibitor PP2 notably blocked IFN-mediated CLL cell survival by downregulating the protein levels of STAT3 and Mcl-1. Our work reveals a novel mechanism of resistance to apoptosis promoted by IFNs in CLL cells, whereby JAKs (TYK2, JAK2) and Src kinases activate in concert a STAT3/Mcl-1 signaling pathway. In view of current clinical developments of potent STAT3 and Mcl-1 inhibitors, a combination of conventional treatments with these inhibitors might thus constitute a new therapeutic strategy in CLL.

Published
2021
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21. Long-term follow up of the CLL2007FMP trial evaluating fludarabine and cyclophosphamide in combination with either rituximab or alemtuzumab in previously untreated patients with chronic lymphocytic leukemia

Author

Pierre Feugier, Thérèse Aurran, Béatrice Mahé, Remi Letestu, Florence Nguyen-Khac, Bruno Cazin, Olivier Tournilhac, Hervé Maisonneuve, Olivier Casasnovas, Alain Delmer, Véronique Leblond, Bruno Royer, Bernadette Corront, Sylvie Chevret, Roselyne Delépine, Sandrine Vaudaux, Eric Van Den Neste, Marie-Christine Béné, Florence Cymbalista, Damien Roos-Weil, and Stéphane Leprêtre

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2018
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22. No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(immuno)therapy

Author

Panagiotis Baliakas, Mattias Mattsson, Anastasia Hadzidimitriou, Eva Minga, Andreas Agathangelidis, Lesley-Ann Sutton, Lydia Scarfo, Zadie Davis, Xiao-Jie Yan, Karla Plevova, Yorick Sandberg, Fie J. Vojdeman, Tatiana Tzenou, Charles C. Chu, Silvio Veronese, Larry Mansouri, Karin E Smedby, Véronique Giudicelli, Florence Nguyen-Khac, Panagiotis Panagiotidis, Gunnar Juliusson, Achilles Anagnostopoulos, Marie-Paule Lefranc, Livio Trentin, Mark Catherwood, Marco Montillo, Carsten U. Niemann, Anton W. Langerak, Sarka Pospisilova, Niki Stavroyianni, Nicholas Chiorazzi, David Oscier, Diane F Jelinek, Tait Shanafelt, Nikos Darzentas, Chrysoula Belessi, Frederic Davi, Paolo Ghia, Richard Rosenquist, and Kostas Stamatopoulos

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2018
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23. Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

Author

Lesley-Ann Sutton, Emma Young, Panagiotis Baliakas, Anastasia Hadzidimitriou, Theodoros Moysiadis, Karla Plevova, Davide Rossi, Jana Kminkova, Evangelia Stalika, Lone Bredo Pedersen, Jitka Malcikova, Andreas Agathangelidis, Zadie Davis, Larry Mansouri, Lydia Scarfò, Myriam Boudjoghra, Alba Navarro, Alice F. Muggen, Xiao-Jie Yan, Florence Nguyen-Khac, Marta Larrayoz, Panagiotis Panagiotidis, Nicholas Chiorazzi, Carsten Utoft Niemann, Chrysoula Belessi, Elias Campo, Jonathan C. Strefford, Anton W. Langerak, David Oscier, Gianluca Gaidano, Sarka Pospisilova, Frederic Davi, Paolo Ghia, Kostas Stamatopoulos, and Richard Rosenquist

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

We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobulin genes, i.e. #1, #6, #8 and #59 (22–34%), often in association with trisomy 12, and was significantly different (P

Published
2016
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24. Additional trisomies amongst patients with chronic lymphocytic leukemia carrying trisomy 12: the accompanying chromosome makes a difference

Author

Panagiotis Baliakas, Anna Puiggros, Aliki Xochelli, Lesley-Ann Sutton, Florence Nguyen-Khac, Anne Gardiner, Karla Plevova, Eva Minga, Anastasia Hadzidimitriou, Renata Walewska, Helen McCarthy, Margarita Ortega, Rosa Collado, Teresa González, Isabel Granada, Elisa Luño, Jana Kotašková, Theodoros Moysiadis, Zadie Davis, Niki Stavroyianni, Achilles Anagnostopoulos, Jonathan C. Strefford, Sarka Pospisilova, Frederic Davi, Anastasia Athanasiadou, Richard Rosenquist, David Oscier, Blanca Espinet, and Kostas Stamatopoulos

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2016
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25. 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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26. STAT3 mutations identified in human hematologic neoplasms induce myeloid malignancies in a mouse bone marrow transplantation model

Author

Lucile Couronné, Laurianne Scourzic, Camilla Pilati, Véronique Della Valle, Yannis Duffourd, Eric Solary, William Vainchenker, Jean-Philippe Merlio, Marie Beylot-Barry, Frederik Damm, Marc-Henri Stern, Philippe Gaulard, Laurence Lamant, Eric Delabesse, Hélène Merle-Beral, Florence Nguyen-Khac, Michaëla Fontenay, Hervé Tilly, Christian Bastard, Jessica Zucman-Rossi, Olivier A. Bernard, and Thomas Mercher

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

STAT3 protein phosphorylation is a frequent event in various hematologic malignancies and solid tumors. Acquired STAT3 mutations have been recently identified in 40% of patients with T-cell large granular lymphocytic leukemia, a rare T-cell disorder. In this study, we investigated the mutational status of STAT3 in a large series of patients with lymphoid and myeloid diseases. STAT3 mutations were identified in 1.6% (4 of 258) of patients with T-cell neoplasms, in 2.5% (2 of 79) of patients with diffuse large B-cell lymphoma but in no other B-cell lymphoma patients (0 of 104) or patients with myeloid malignancies (0 of 96). Functional in vitro assays indicated that the STAT3Y640F mutation leads to a constitutive phosphorylation of the protein. STA21, a STAT3 small molecule inhibitor, inhibited the proliferation of two distinct STAT3 mutated cell lines. Using a mouse bone marrow transplantation assay, we observed that STAT3Y640F expression leads to the development of myeloproliferative neoplasms with expansion of either myeloid cells or megakaryocytes. Together, these data indicate that the STAT3Y640F mutation leads to constitutive activation of STAT3, induces malignant hematopoiesis in vivo, and may represent a novel therapeutic target in some lymphoid malignancies.

Published
2013
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27. 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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28. 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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29. 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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30. Transcriptional activation of the cardiac homeobox gene CSX1/NKX2-5 in a B-cell chronic lymphoproliferative disorder

Author

Xinying Su, Véronique Della-Valle, Eric Delabesse, Zahia Azgui, Roland Berger, Hélène Merle-Béral, Olivier A Bernard, and Florence Nguyen-Khac

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

Homeobox containing transcription factors are frequently deregulated in human hematologic malignant diseases either indirectly through an abnormality of an upstream factor, or directly through rearrangement of the gene itself. Study of T-cell acute lymphoblastic leukemia identified the related non-clustered homeobox transcription factors, TLX1 and TLX3, as frequently ectopically expressed as a result of chromosomal translocations. We report the deregulation of a non-clustered homeobox gene in a new type of t(5;14)(q35;q11) translocation in a mature peripheral B-cell leukemia. This translocation results in the ectopic expression of the CSX1/NKX2-5 gene on chromosome 5q35 due to its juxtaposition to the TCR δ gene on chromosome 14q11. Expression of the CSX1/NKX2-5 protein conferred enhanced replating potential to transduced murine bone marrow cells. Our study establishes that deregulation of homeobox encoding genes is not restricted to acute leukemic proliferations, but is also observed in chronic malignant diseases.

Published
2008
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31. 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

33. A fixed-duration, immunochemotherapy approach in CLL: 5.5-year results from the phase 2 ICLL-07 FILO trial

Author

Anne-Sophie Michallet, Rémi Letestu, Magali Le Garff-Tavernier, Lydia Campos, Michel Ticchioni, Marie-Sarah Dilhuydy, Stephane MORISSET, Valerie Rouille, Beatrice Mahe, Kamel Laribi, Bruno Villemagne, Emmanuelle France Ferrant, Olivier Tournilhac, Alain Jacques Delmer, Lysiane Molina, Veronique Leblond, Cécile TOMOWIAK, Sophie De Guibert, Frederique Orsini Piocelle, Anne Banos, Philippe Carassou, Guillaume Cartron, Luc-Matthieu Fornecker, Loïc Ysebaert, Caroline Dartigeas, Malgorzata Truchan-Graczyk, Jean-Pierre Vilque, Thérèse Aurran Schleinitz, Florence Cymbalista, Stéphane Leprêtre, Vincent Lévy, Florence Nguyen-Khac, and Pierre Feugier

Subjects
Hematology
Abstract

In previously untreated, medically fit patients with chronic lymphocytic leukemia, research is focused on developing fixed-duration strategies to improve long-term outcomes whilst sparing patients from serious toxicities. The ICLL-07 trial evaluated a fixed-duration (15-month) immunochemotherapy approach where, following obinutuzumab-ibrutinib induction for 9 months, patients (n=10) in complete remission (CR) with bone marrow (BM) measurable residual disease (MRD)

Published
2023

34. Supplementary Table S5 from Acquired Initiating Mutations in Early Hematopoietic Cells of CLL Patients

Author

Olivier A. Bernard, Florence Nguyen-Khac, Seishi Ogawa, Nathalie Droin, Thomas Mercher, William Vainchenker, Koichi Akashi, Eric Solary, Philippe Dessen, Laurent Sutton, Hélène Merle-Béral, Daniel Gautheret, Jérôme Lambert, Frederick Davi, Yoshikane Kikushige, Satoru Miyano, Hiroko Tanaka, Kenichi Chiba, Yuichi Shiraishi, Laurianne Scourzic, M'boyba Diop, Enguerran Mouly, Véronique Della Valle, Kenichi Yoshida, Adrien Cosson, Elena Mylonas, and Frederik Damm

Abstract

XLS file - 75KB, Details of signature and expression analyses.

Published
2023

35. Supplementary Figure S1 from Acquired Initiating Mutations in Early Hematopoietic Cells of CLL Patients

Author

Olivier A. Bernard, Florence Nguyen-Khac, Seishi Ogawa, Nathalie Droin, Thomas Mercher, William Vainchenker, Koichi Akashi, Eric Solary, Philippe Dessen, Laurent Sutton, Hélène Merle-Béral, Daniel Gautheret, Jérôme Lambert, Frederick Davi, Yoshikane Kikushige, Satoru Miyano, Hiroko Tanaka, Kenichi Chiba, Yuichi Shiraishi, Laurianne Scourzic, M'boyba Diop, Enguerran Mouly, Véronique Della Valle, Kenichi Yoshida, Adrien Cosson, Elena Mylonas, and Frederik Damm

Abstract

PDF file - 126KB, Analyses of two patients with detectable SF3B1 mutations in CD19+, CD34+ and CD14+ fractions.

Published
2023

36. A Fixed-Duration Immunochemotherapy Approach Combined with Ibrutinib in CLL Produces Deep and Sustained MRD Responses: 5.5-Year Results from the Icll-07 Filo Trial

Author

Anne-Sophie Michallet, Rémi Letestu, Magali Le Garff-Tavernier, Carmen Aanaei, Michel Ticchioni, Marie-Sarah Dilhuydy, Stephane Morisset, Valérie Rouille, Béatrice Mahé, Kamel Laribi, Bruno Villemagne, Emmanuelle Ferrant, Olivier Tournilhac, Alain Delmer, Christelle Portois, Lysiane Molina, Véronique Leblond, Cécile Tomowiak, Sophie de Guibert, Frederique Orsini, Anne Banos, Philippe Carassou, Guillaume Cartron, Luc Mathieu Fornecker, Loic Ysebaert, Caroline Dartigeas, Margot Truchan, Jean-Pierre Vilque, Therese Aurran Schleinitz, Cymbalista Florence, Stéphane Leprêtre, Vincent Lévy, Florence Nguyen Khac, and Pierre Feugier

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

37. Preliminary Results of the Filo Phase 2 Trial for Untreated Fit Patients with Intermediate Risk Chronic Lymphocytic Leukemia Comparing Ibrutinib Plus Venetoclax (IV) Versus FCR: Results of the Month 15 MRD Evaluation

Author

Anne Quinquenel, Rémi Letestu, Magali Le Garff-Tavernier, Fabien Subtil, Therese Aurran-Schleinitz, Kamel Laribi, Florence Cymbalista, Vincent Levy, Laurence Simon, Damien Roos-Weil, Véronique Leblond, Marie-Sarah Dilhuydy, Caroline Dartigeas, Cecile Tomowiak, Romain Guieze, Olivier Tournilhac, Emmanuelle Ferrant, Sophie de Guibert, Pierre Feugier, Fatiha Merabet, Stephane Lepretre, Philippe Carassou, Julie Gay, Bénédicte Hivert, Luc Mathieu Fornecker, Jehan Dupuis, Lysiane Molina, Bruno Villemagne, Guillaume Cartron, Bernard Drenou, Béatrice Mahé, Omar Benbrahim, Xavier Cahu, Christelle Portois, Loic Ysebaert, Florence Nguyen Khac, Valérie Rouille, Alain Delmer, and Anne-Sophie Michallet

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

38. Correction : Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY

Author

Larry Mansouri, Birna Thorvaldsdottir, Lesley-Ann Sutton, Georgios Karakatsoulis, Manja Meggendorfer, Helen Parker, Ferran Nadeu, Christian Brieghel, Stamatia Laidou, Riccardo Moia, Davide Rossi, Mark Catherwood, Jana Kotaskova, Julio Delgado, Ana E. Rodríguez-Vicente, Rocío Benito, Gian Matteo Rigolin, Silvia Bonfiglio, Lydia Scarfo, Mattias Mattsson, Zadie Davis, Ajay Gogia, Lata Rani, Panagiotis Baliakas, Hassan Foroughi-Asl, Cecilia Jylhä, Aron Skaftason, Inmaculada Rapado, Fatima Miras, Joaquín Martinez-Lopez, Javier de la Serna, Jesús María Hernández Rivas, Patrick Thornton, María José Larráyoz, María José Calasanz, Viktória Fésüs, Zoltán Mátrai, Csaba Bödör, Karin E. Smedby, Blanca Espinet, Anna Puiggros, Ritu Gupta, Lars Bullinger, Francesc Bosch, Bárbara Tazón-Vega, Fanny Baran-Marszak, David Oscier, Florence Nguyen-Khac, Thorsten Zenz, Maria Jose Terol, Antonio Cuneo, María Hernández-Sánchez, Sarka Pospisilova, Ken Mills, Gianluca Gaidano, Carsten U. Niemann, Elias Campo, Jonathan C. Strefford, Paolo Ghia, Kostas Stamatopoulos, and Richard Rosenquist

Subjects
Cancer Research, Oncology, Genetics research, Hematology, Cancer genetics
Published
2023

39. 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

41. TP53 Abnormalities are underlying the poor outcome associated with chromothripsis in chronic lymphocytic Leukemia patients with complex karyotype

Author

Silvia Ramos-Campoy, Anna Puiggros, Joanna Kamaso, Sílvia Beà, Sandrine Bougeon, María José Larráyoz, Dolors Costa, Helen Parker, Gian Matteo Rigolin, María Laura Blanco, Rosa Collado, Idoya Ancín, Rocío Salgado, Marco A. Moro-García, Tycho Baumann, Eva Gimeno, Carol Moreno, Marta Salido, Xavier Calvo, María José Calasanz, Antonio Cuneo, Florence Nguyen-Khac, David Oscier, Claudia Haferlach, Jonathan C. Strefford, Jacqueline Schoumans, and Blanca Espinet

Subjects
Cancer Research, Chromothripsis, Oncology, Genomic complexity, chronic lymphocytic leukemia, genomic complexity, chromothripsis, TP53, genomic microarrays, optical genome mapping, Optical genome mapping, Chronic lymphocytic leukemia, Genomic microarrays
Abstract

Simple Summary Chromothripsis, a genomic event that generates massive chromosomal rearrangements, has been described in 1-3% of CLL patients and is associated with poor prognostic factors (e.g., TP53 abnormalities and genomic complexity). However, previous studies have not assessed its role in CLL patients with complex karyotypes. Herein, we aimed to describe the genetic characteristics of 33 CLL patients with high genomic complexity and chromothripsis. Moreover, we analyzed the clinical impact of chromothripsis, comparing these patients against a cohort of 129 patients with complex karyotypes not presenting this catastrophic event. Nine cases were also assessed via the novel cytogenomic methodology known as optical genome mapping. We confirmed that this phenomenon is heterogeneous and associated with a shorter time to first treatment. Nonetheless, our findings suggested that TP53 abnormalities, rather than chromothripsis itself, underlie the dismal outcome. Chromothripsis (cth) has been associated with a dismal outcome and poor prognosis factors in patients with chronic lymphocytic leukemia (CLL). Despite being correlated with high genome instability, previous studies have not assessed the role of cth in the context of genomic complexity. Herein, we analyzed a cohort of 33 CLL patients with cth and compared them against a cohort of 129 non-cth cases with complex karyotypes. Nine cth cases were analyzed using optical genome mapping (OGM). Patterns detected by genomic microarrays were compared and the prognostic value of cth was analyzed. Cth was distributed throughout the genome, with chromosomes 3, 6 and 13 being those most frequently affected. OGM detected 88.1% of the previously known copy number alterations and several additional cth-related rearrangements (median: 9, range: 3-26). Two patterns were identified: one with rearrangements clustered in the region with cth (3/9) and the other involving both chromothriptic and non-chromothriptic chromosomes (6/9). Cases with cth showed a shorter time to first treatment (TTFT) than non-cth patients (median TTFT: 2 m vs. 15 m; p = 0.013). However, when stratifying patients based on TP53 status, cth did not affect TTFT. Only TP53 maintained its significance in the multivariate analysis for TTFT, including cth and genome complexity defined by genomic microarrays (HR: 1.60; p = 0.029). Our findings suggest that TP53 abnormalities, rather than cth itself, underlie the poor prognosis observed in this subset.

Published
2022

42. Leucémie prolymphocytaire B

Author

Florence Nguyen-Khac and Élise Chapiro

Subjects
Medical Laboratory Technology, Biochemistry (medical), Analytical Chemistry
Published
2021

43. Chromosome banding analysis and genomic microarrays are both useful but not equivalent methods for genomic complexity risk stratification in chronic lymphocytic leukemia patients

Author

Eva Gimeno, Margarita Ortega, Silvia Ramos-Campoy, Francesc Bosch, Tycho Baumann, Sandrine Bougeon, Florence Nguyen-Khac, Helen Parker, Carolina Moreno, Anna Puiggros, Blanca Espinet, Xavier Calvo, María José Calasanz, María José Larrayoz, David Oscier, Rosa Collado, Claudia Haferlach, María Laura Blanco, Jacqueline Schoumans, Rocío Salgado, Gian Matteo Rigolin, Sílvia Beà, Antonio Cuneo, Jonathan C. Strefford, Dolors Costa, Institut Català de la Salut, [Ramos-Campoy S, Puiggros A] Molecular Cytogenetics Laboratory, Pathology Department, Hospital del Mar, Barcelona, Spain. Translational Research on Hematological Neoplasms Group, Cancer Research Program, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain. [Beà S, Costa D] Hematopathology Unit, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona, Spain. [Bougeon S] Oncogenomic Laboratory, Hematology Service, Lausanne University Hospital, Lausanne, Switzerland. [Larráyoz MJ] Cytogenetics and Hematological Genetics Services, Department of Genetics, University of Navarra, Pamplona, Spain. [Ortega M, Bosch F] Servei d’Hematologia, Vall d'Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Oncology, medicine.medical_specialty, Chronic lymphocytic leukemia, Leucèmia limfocítica crònica - Aspectes genètics, Biology, Genetic Phenomena::Genetic Variation::Mutation::Chromosome Aberrations [PHENOMENA AND PROCESSES], Risk Assessment, NO, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Complex Karyotype, Other subheadings::Other subheadings::/genetics [Other subheadings], medicine, Humans, In patient, microarrays, Chromosome Aberrations, Natural Science Disciplines::Biological Science Disciplines::Biology::Computational Biology::Genomics [DISCIPLINES AND OCCUPATIONS], Chronic lymphocytic leukmia, genomic complexity, Genome complexity, Otros calificadores::Otros calificadores::/genética [Otros calificadores], Karyotype, Genomics, Hematology, Prognosis, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Chromosome Banding, Genòmica, Anomalies cromosòmiques, Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Lymphoid::Leukemia, B-Cell::Leukemia, Lymphocytic, Chronic, B-Cell [DISEASES], Área de Biomedicina, 030220 oncology & carcinogenesis, disciplinas de las ciencias naturales::disciplinas de las ciencias biológicas::biología::biología computacional::genómica [DISCIPLINAS Y OCUPACIONES], Mutation, Risk stratification, Cohort, DNA microarray, fenómenos genéticos::variación genética::mutación::aberraciones cromosómicas [FENÓMENOS Y PROCESOS], neoplasias::neoplasias por tipo histológico::leucemia::leucemia linfoide::leucemia de células B::leucemia linfocítica crónica de células B [ENFERMEDADES], 030215 immunology
Abstract

Genome complexity has been associated with poor outcome in patients with chronic lymphocytic leukemia (CLL). Previous cooperative studies established five abnormalities as the cut-off that best predicts an adverse evolution by chromosome banding analysis (CBA) and genomic microarrays (GM). However, data comparing risk stratification by both methods are scarce. Herein, we assessed a cohort of 340 untreated CLL patients highly enriched in cases with complex karyotype (CK) (46.5%) with parallel CBA and GM studies. Abnormalities found by both techniques were compared. Prognostic stratification in three risk groups based on genomic complexity (0-2, 3-4 >= 5 and abnormalities) was also analyzed. No significant differences in the percentage of patients in each group were detected, but only a moderate agreement was observed between methods when focusing on individual cases (kappa=0.507; P

Published
2021

45. 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

46. Therapy-related Myeloid Neoplasms in Patients With Chronic Lymphocytic Leukemia Who Received FCR/FC as Frontline Therapy

Author

Kamel Laribi, Alix Baugier de Materre, David Ghez, Caroline Dartigeas, Cécile Tomowiak, Béatrice Mahé, Jean-Baptiste Micol, Fatiha Merabet, Stéphane Leprêtre, Charles Herbaux, Loïc Ysebaert, Ronan Le Calloch, Lise Willems, Maud Voldoire, Damien Roos-Weil, Clotilde Bravetti, Yamina Touileb, Frédéric Davi, Florence Nguyen-Khac, Karim Maloum, and Marie C. Béné

Subjects
Hematology
Published
2021

47. 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

48. A Recurrent Activating Missense Mutation in Waldenström Macroglobulinemia Affects the DNA Binding of the ETS Transcription Factor SPI1 and Enhances Proliferation

Author

Nathalie Droin, Philippe Rameau, Philippe Dessen, Florence Nguyen-Khac, Bilyana Stoilova, Elena Mylonas, Marine Armand, Damien Roos-Weil, Olivier Bernard, Els Verhoeyen, Paresh Vyas, Said Aoufouchi, Marlen Metzner, Françoise Pflumio, Frédéric Charlotte, Vincent Ribrag, Diane Lara, Olivier Elemento, Pierre Morel, Eric Durot, Cécile Hérate, Pascale Cornillet-Lefebvre, Véronique Della-Valle, Hussein Ghamlouch, Virginie Ropars, Frederik Damm, Nabih Azar, Christel Guillouf, François-Loïc Cosset, Camille Decaudin, Valérie Camara-Clayette, M'Boyba Diop, Veronique Leblond, Thomas Mercher, Jean-Baptiste Charbonnier, Rima Haddad, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Enveloppe Nucléaire, Télomères et Réparation de l’ADN (INTGEN), Département Biochimie, Biophysique et Biologie Structurale (B3S), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Department of Haematology, Haemostasis, Oncology and Stem Cell Transplantation (MHH), Hannover Medical School [Hannover] (MHH), CEA Direction des Sciences du Vivant (CEA/DSV), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), The Weatherall Institute of Molecular Medicine, University of Oxford [Oxford], Weill Medical College of Cornell University [New York], Institut Gustave Roussy (IGR), Plateforme de Bioinformatique [Gustave Roussy], 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)-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), Laboratoire de recherche translationnelle (Labo RT), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Sorbonne Université (SU), Département d'hématologie [Gustave Roussy], Laboratoire d'hématologie, Centre Hospitalier Universitaire de Reims (CHU Reims), Plateforme imagerie et cytométrie (PFIC), Ligue Nationale Contre le Cancer - Paris, Ligue Nationale Contre le Cancer (LNCC), Brigham and Women's Hospital [Boston], Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie Biologique [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)-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), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-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)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), 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)-Sorbonne Université (SU), Ligue Nationnale Contre le Cancer, Centre de Recherche et d'Etude en Droit et Science Politique (CREDESPO), Université de Bourgogne (UB), University of Oxford, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and École Pratique des Hautes Études (EPHE)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Mutation, Missense, lymphoma, Biology, Cell Line, Mice, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Mutant protein, Proto-Oncogene Proteins, spi-1/pu.1, pu.1, Animals, Humans, somatic mutation, Nucleotide Motifs, Lenalidomide, Transcription factor, mouse, Cell Proliferation, cll, B-Lymphocytes, Binding Sites, SPI1, Base Sequence, Proto-Oncogene Proteins c-ets, Point mutation, ETS transcription factor family, Promoter, Azepines, Triazoles, Cell biology, cell differentiation, 030104 developmental biology, Gene Expression Regulation, Oncology, 030220 oncology & carcinogenesis, Myeloid Differentiation Factor 88, Trans-Activators, acute myeloid-leukemia, Waldenstrom Macroglobulinemia, Transcription Factor Gene, Protein Binding, Transcription Factors
Abstract

The ETS-domain transcription factors divide into subfamilies based on protein similarities, DNA-binding sequences, and interaction with cofactors. They are regulated by extracellular clues and contribute to cellular processes, including proliferation and transformation. ETS genes are targeted through genomic rearrangements in oncogenesis. The PU.1/SPI1 gene is inactivated by point mutations in human myeloid malignancies. We identified a recurrent somatic mutation (Q226E) in PU.1/SPI1 in Waldenström macroglobulinemia, a B-cell lymphoproliferative disorder. It affects the DNA-binding affinity of the protein and allows the mutant protein to more frequently bind and activate promoter regions with respect to wild-type protein. Mutant SPI1 binding at promoters activates gene sets typically promoted by other ETS factors, resulting in enhanced proliferation and decreased terminal B-cell differentiation in model cell lines and primary samples. In summary, we describe oncogenic subversion of transcription factor function through subtle alteration of DNA binding leading to cellular proliferation and differentiation arrest. Significance: The demonstration that a somatic point mutation tips the balance of genome-binding pattern provides a mechanistic paradigm for how missense mutations in transcription factor genes may be oncogenic in human tumors. This article is highlighted in the In This Issue feature, p. 681

Published
2019

49. 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

50. Real-world outcomes following venetoclax therapy in patients with chronic lymphocytic leukemia or Richter syndrome: a FILO study of the French compassionate use cohort

Author

Sophie de Guibert, Lauren Veronese, Loic Ysebaert, Charles Herbaux, Olivier Tournilhac, Emmanuelle Tchernonog, Anne-Sophie Michallet, Florence Cymbalista, Damien Roos-Weil, Bruno Pereira, Jehan Dupuis, Pierre Feugier, Anne Calleja, Florian Bouclet, Caroline Dartigeas, Sandy Amorim, Anaise Blouet, Marie-Sarah Dilhuydy, Florence Nguyen-Khac, Pierre Morel, Nataliya Dmytruck, Kamel Laribi, Alain Delmer, Thérèse Aurran, Bénédicte Hivert, Romain Guieze, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne (UCA), and FAYE, Fatimata

Subjects
Oncology, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Compassionate Use Trials, Male, medicine.medical_treatment, Chronic lymphocytic leukemia, Abnormal Karyotype, Kaplan-Meier Estimate, Targeted therapy, law.invention, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Medicine, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, Sulfonamides, Hematology, Hematopoietic Stem Cell Transplantation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Medicine, Middle Aged, Progression-Free Survival, 3. Good health, Tumor lysis syndrome, Treatment Outcome, 030220 oncology & carcinogenesis, Cohort, Female, France, Lymphoma, Large B-Cell, Diffuse, Adult, medicine.medical_specialty, Antineoplastic Agents, Infections, 03 medical and health sciences, Internal medicine, Complex Karyotype, Humans, Aged, Retrospective Studies, business.industry, Venetoclax, medicine.disease, Bridged Bicyclo Compounds, Heterocyclic, Genes, p53, Leukemia, Lymphocytic, Chronic, B-Cell, chemistry, Drug Evaluation, business, Tumor Lysis Syndrome, 030215 immunology
Abstract

The BCL2 inhibitor venetoclax is transforming the management of patients with chronic lymphocytic leukemia (CLL), given its high efficacy in relapsed/refractory CLL as observed in both early-phase and randomized clinical trials. The present study aimed to determine whether venetoclax is effective and well tolerated in patients with CLL or Richter's syndrome (RS) in a real-world setting and to highlight factors impacting survival. Data from a venetoclax French compassionate use program were collected for 67 patients (60 with CLL and 7 with RS). Most patients presented adverse genetic features, such as TP53 disruption (74%) or complex karyotype (58%). Tumor lysis syndrome was observed in 14 (22%) patients, and 16 (24%) patients were hospitalized for grade III/IV infection. In the CLL cohort, ORR was 75 %, 1-year PFS was 61% (95% CI = 47-72%) and 1-year OS 70% (95% CI = 56-80%). No impact of TP53 disruption was noted while complex karyotype was identified as a predictor of both inferior PFS (HR = 3.46; 95% CI = 1-12; log-rank p = 0.03) and OS (HR = 3.2; 95% CI = 0.9-11.4, log-rank p = 0.047). Among the seven patients with RS, two achieved an objective response to venetoclax; however, the median OS was only 1.1 month. The well-balanced safety/efficacy profile of venetoclax is confirmed in this real-world setting. Complex karyotype should be evaluated as a predictive factor of survival for patients treated by venetoclax.

Published
2021

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