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1. Flow cytometric analysis of peripheral blood neutrophil myeloperoxidase expression in myelodysplastic neoplasms (MPO-MDS-Valid): protocol for a multicentre diagnostic accuracy study

Author

Sophie Park, José Labarère, Arnaud Seigneurin, Lydia Campos, Raymond Merle, Tatiana Raskovalova, Marie-Christine Jacob, Sylvie Tondeur, Charlotte Planta, Nicolas Gonnet, Caroline Bret, Delphine Manzoni, Anne-Catherine Lhoumeau, Caroline Mayeur Rousse, Michel Ticchioni, Alice Eischen, Franciane Paul, Estelle Comte, Alessandra Allieri-Rosenthal, and Chloé Regnart

Subjects
Medicine
Abstract

Introduction Many patients referred for suspicion of myelodysplastic neoplasm (MDS) are subjected to unnecessary discomfort from bone marrow aspiration, due to the low disease prevalence in this population. Flow cytometric analysis of peripheral blood neutrophil myeloperoxidase expression could rule out MDS with sensitivity and negative predictive value estimates close to 100%, ultimately obviating the need for bone marrow aspiration in up to 35% of patients. However, the generalisability of these findings is uncertain due to the limited sample size, the enrolment of patients at a single study site, and the reliability issues associated with laboratory-developed tests and varying levels of operator experience. This study aims to validate the accuracy attributes of peripheral blood neutrophil myeloperoxidase expression quantified by flow cytometric analysis in an independent multicentre sample.Methods and analysis The MPO-MDS-Valid project is a cross-sectional diagnostic accuracy study comparing an index test to a reference standard. Consecutive adult patients referred for suspicion of MDS are being recruited at seven university hospitals and one cancer centre in France. At each site, flow cytometric analysis of peripheral blood samples is performed by operators who are blinded to the reference diagnosis. A central adjudication committee whose members are unaware of the index test results will determine the reference diagnosis of MDS, based on cytomorphological evaluation of bone marrow performed in duplicate by experienced hematopathologists. The target sample size is 400 patients and the anticipated study recruitment completion date is 31 December 2025.Ethics and dissemination An institutional review board (Comité de Protection des Personnes Nord-Ouest III, Caen, France) approved the protocol, prior to the start of the study. Participants are recruited using an opt-out approach. Efforts will be made to publish the primary results within 6 months after study completion.Trial registration number NCT05175469.

Published
2024
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3. AML with inv(16)/t(16;16) and high-risk cytogenetic abnormalities: atypical features and unfavorable outcome

Author

Nada Assaf, Christine Lefebvre, Victoria Raggueneau, Geoffroy Guignedoux, Alice Marceau-Renaut, Simon Chevalier, Sylvie Tondeur, Dominique Bories, Riad Benramdane, Philippe Rousselot, and Christine Terré

Subjects
Acute myeloid leukemia, inv(16), CBFB-MYH11, cytogenetic aberrations, complex karyotype, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Objectives Acute myeloid leukemia (AML) with inv(16)/t(16;16) is among the most frequent AML subtypes. It is recognized by the detection of the CBFB-MYH11 fusion which confers a favorable prognosis, irrespective of the presence of secondary cytogenetic abnormalities. However, the effect of additional genetic anomalies on the behavior of inv(16) AML is debatable. Recent case reports describe an unfavorable prognosis for those patients, characterized by early relapse and death. In this study, we present a series of patients with CBFB-MYH11 fusion and high-risk rearrangements to increase knowledge about this potentially distinct subgroup.Methods All cases with inv(16)/ t(16;16) and one or more high risk abnormalities were reviewed at two tertiary healthcare centers between years 2006 and 2020 in terms of demographics, biological and clinical data.Results Among the total 1447 and 1283 AML cases, the frequency was found to be 0,2% and 0.3%. Clinical data could be retrieved for 5 patients. Detected high-risk abnormalities included TP53 and 5q deletion, complex and monosomal karyotype. The median age was 67 years, with a majority of females (M:F = 1:1.5). Two out of 5 patients presented with therapy related AML, with short latency periods. All patients presented with thrombocytopenia and/or leukocytopenia. Bone marrow aspirates revealed atypical morphology and the detection of rare CBFB-MYH11 fusion transcripts. All 5 patients died, with a short mean overall survival of 5.8 months.Discussion and Conclusion Our series suggests that the presence of high risk abnormalities confers distinct biological features and poor prognosis to inv(16) AML.

Published
2022
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4. Flow cytometry lyophilised-reagent tube for quantifying peripheral blood neutrophil myeloperoxidase expression in myelodysplastic syndromes (MPO-MDS-Develop): protocol for a diagnostic accuracy study

Author

Sophie Park, José Labarère, Raymond Merle, Tatiana Raskovalova, Laura Scheffen, Marie-Christine Jacob, Simon Chevalier, Sylvie Tondeur, Bénédicte Bulabois, Mathieu Meunier, Gautier Szymanski, Christine Lefebvre, Charlotte Planta, Chantal Dumestre-Perard, Nicolas Gonnet, and Frédéric Garban

Subjects
Medicine
Abstract

Introduction Suspicion of myelodysplastic syndromes (MDS) is the most common reason for bone marrow aspirate in elderly patients. Peripheral blood neutrophil myeloperoxidase expression quantified by flow cytometric analysis might rule out MDS for up to 35% of patients referred for suspected disease, without requiring bone marrow aspiration. Yet laboratory-developed liquid antibody cocktails have practical limitations, because of lack of standardisation and poor stability. This research project aims to estimate the level of agreement and comparative accuracy between a single-use flow cytometry tube of lyophilised reagents (BD Lyotube Stain 468) and its laboratory-developed liquid reagent counterpart in quantifying peripheral blood neutrophil myeloperoxidase expression, among adult patients referred for suspected MDS.Methods and analysis The MPO-MDS-Develop project is a cross-sectional diagnostic accuracy study of two index tests by comparison with a reference standard in consecutive unselected adult patients conducted at a single university hospital. Flow cytometry analysis of peripheral blood samples will be performed by independent operators blinded to the reference diagnosis, using either Lyotube Stain 468 or laboratory-developed liquid reagent cocktail. The reference diagnosis of MDS will be established by cytomorphological evaluation of bone marrow aspirate by two independent haematopathologists blinded to the index test results. Morphologic assessment will be complemented by bone marrow flow cytometric score, karyotype and targeted next-generation sequencing panel of 43 genes, where relevant. The target sample size is 103 patients.Ethics and dissemination An institutional review board (Comité de Protection des Personnes Sud Est III, Lyon, France) approved the protocol prior to study initiation (reference number: 2020-028-B). Participants will be recruited using an opt-out approach. Efforts will be made to release the primary results within 6 months of study completion.Trial registration number NCT04399018.

Published
2022
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5. 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

6. 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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7. Evaluation by Flow Cytometry of Mature Monocyte Subpopulations for the Diagnosis and Follow-Up of Chronic Myelomonocytic Leukemia

Author

Tiphanie Picot, Carmen Mariana Aanei, Pascale Flandrin Gresta, Pauline Noyel, Sylvie Tondeur, Emmanuelle Tavernier Tardy, Denis Guyotat, and Lydia Campos Catafal

Subjects
chronic myelomonocytic leukemia, flow cytometry, monocytic subpopulations, peripheral blood monocytosis, next-generation sequencing, karyotype, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm, characterized by persistent monocytosis and dysplasia in at least one myeloid cell lineage. This persistent monocytosis should be distinguished from the reactive monocytosis which is sometimes observed in a context of infections or solid tumors. In 2015, Selimoglu-Buet et al. observed an increased percentage of classical monocytes (CD14+/CD16− >94%) in the peripheral blood (PB) of CMML patients. In this study, using multiparametric flow cytometry (MFC), we assessed the monocytic distribution in PB samples and in bone marrow aspirates from 63 patients with monocytosis or CMML suspicion, and in seven follow-up blood samples from CMML patients treated with hypomethylating agents (HMA). A control group of 12 healthy age-matched donors was evaluated in parallel in order to validate the analysis template. The CMML diagnosis was established in 15 cases in correlation with other clinical manifestations and biological tests. The MFC test for the evaluation of the repartition of monocyte subsets, as previously described by Selimoglu-Buet et al. showed a specificity of 97% in blood and 100% in marrow samples. Additional information regarding the expression of intermediate MO2 monocytes percentage improved the specificity to 100% in blood samples allowing the screening of abnormal monocytosis. The indicative thresholds of CMML monocytosis were different in PB compared to BM samples (classical monocytes >95% for PB and >93% for BM). A decrease of monocyte levels in PB and BM, along with a normalization of monocytes distribution, was observed after treatment in 4/7 CMML patients with favorable evolution. No significant changes were observed in 3/7 patients who did not respond to HMA therapy and also presented unfavorable molecular prognostic factors at diagnosis (ASXL1, TET2, and IDH2 mutations). Considering its simplicity and robustness, the monocyte subsets evaluation by MFC provides relevant information for CMML diagnosis.

Published
2018
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8. 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

9. Flow cytometry lyophilised-reagent tube for quantifying peripheral blood neutrophil myeloperoxidase expression in myelodysplastic syndromes (MPO-MDS-Develop): protocol for a diagnostic accuracy study

Author

Tatiana Raskovalova, Laura Scheffen, Marie-Christine Jacob, Simon Chevalier, Sylvie Tondeur, Bénédicte Bulabois, Mathieu Meunier, Gautier Szymanski, Christine Lefebvre, Charlotte Planta, Chantal Dumestre-Perard, Nicolas Gonnet, Frédéric Garban, Raymond Merle, Sophie Park, and José Labarère

Subjects
Adult, Cross-Sectional Studies, Neutrophils, Myelodysplastic Syndromes, Humans, Indicators and Reagents, General Medicine, Flow Cytometry, Aged, Peroxidase
Abstract

IntroductionSuspicion of myelodysplastic syndromes (MDS) is the most common reason for bone marrow aspirate in elderly patients. Peripheral blood neutrophil myeloperoxidase expression quantified by flow cytometric analysis might rule out MDS for up to 35% of patients referred for suspected disease, without requiring bone marrow aspiration. Yet laboratory-developed liquid antibody cocktails have practical limitations, because of lack of standardisation and poor stability. This research project aims to estimate the level of agreement and comparative accuracy between a single-use flow cytometry tube of lyophilised reagents (BD Lyotube Stain 468) and its laboratory-developed liquid reagent counterpart in quantifying peripheral blood neutrophil myeloperoxidase expression, among adult patients referred for suspected MDS.Methods and analysisThe MPO-MDS-Develop project is a cross-sectional diagnostic accuracy study of two index tests by comparison with a reference standard in consecutive unselected adult patients conducted at a single university hospital. Flow cytometry analysis of peripheral blood samples will be performed by independent operators blinded to the reference diagnosis, using either Lyotube Stain 468 or laboratory-developed liquid reagent cocktail. The reference diagnosis of MDS will be established by cytomorphological evaluation of bone marrow aspirate by two independent haematopathologists blinded to the index test results. Morphologic assessment will be complemented by bone marrow flow cytometric score, karyotype and targeted next-generation sequencing panel of 43 genes, where relevant. The target sample size is 103 patients.Ethics and disseminationAn institutional review board (Comité de Protection des Personnes Sud Est III, Lyon, France) approved the protocol prior to study initiation (reference number: 2020-028-B). Participants will be recruited using an opt-out approach. Efforts will be made to release the primary results within 6 months of study completion.Trial registration numberNCT04399018.

Published
2022

10. Expression of embryonic stem cell markers in acute myeloid leukemia

Author

Tiphanie Picot, Carmen Mariana Aanei, Amandine Fayard, Pascale Flandrin-Gresta, Sylvie Tondeur, Marina Gouttenoire, Emmanuelle Tavernier-Tardy, Eric Wattel, Denis Guyotat, and Lydia Campos

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Acute myeloid leukemia is driven by leukemic stem cells which can be identified by cross lineage expression or arrest of differentiation compared to normal hematopoietic stem cells. Self-renewal and lack of differentiation are also features of stem cells and have been associated with the expression of embryonic genes. The aim of our study was to evaluate the expression of embryonic antigens (OCT4, NANOG, SOX2, SSEA1, SSEA3) in hematopoietic stem cell subsets (CD34 + CD38 − and CD34 + CD38 + ) from normal bone marrows and in samples from acute myeloid leukemia patients. We observed an upregulation of the transcription factors OCT4 and SOX2 in leukemic cells as compared to normal cells. Conversely, SSEA1 protein was downregulated in leukemic cells. The expression of OCT4, SOX2, and SSEA3 was higher in CD34 + CD38 − than in CD34 + CD38 + subsets in leukemic cells. There was no correlation with biological characteristics of the leukemia. We evaluated the prognostic value of marker expression in 69 patients who received an intensive treatment. The rate of complete remission was not influenced by the level of expression of markers. Overall survival was significantly better for patients with high SOX2 levels, which was unexpected because of the inverse correlation with favorable genetic subtypes. These results prompt us to evaluate the potential role of these markers in leukemogenesis and to test their relevance for better leukemic stem cell identification.

Published
2017
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12. Thrombosis with Non-Proliferative Complete Blood Count Indicative of Underlying Myeloproliferative Neoplasm, Sythrom, a Study on Behalf of the FIM Group

Author

Yannick LE Bris, Jean Galtier, Dina Naguib, Mathieu Wemeau, Jean Claude Chomel, Laurence Legros, Yan Beauverd, Lise Willems, Guillaume Denis, Françoise Boyer perrard, Damien Luque-Paz, Kamel Laribi, Mélanie Mercier, Pascale Cony-Makhoul, Olivier Herault, Lydia Roy, Pierre Sujobert, Lenaig Le Clech, Sylvie Tondeur, Gaelle Laboure, Jerome Rey, Guillou Sophie, Cedric Pastoret, Pascaline Etancelin, Suzanne Tavitian, Charles Bescond, Francois Girodon, Shanti Amé, Viviane Dubruille, Eric Lippert, Chloe James, Barbara Burroni, Marc Fouassier, Marie C Béné, and Jean Christophe Ianotto

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

13. Mitochondria in human acute myeloid leukemia cell lines have ultrastructural alterations linked to deregulation of their respiratory profiles

Author

Sylvie Tondeur, Caroline Lo Presti, Karin Pernet-Gallay, Anne Mc Leer, Sandrine Blanchet, Julie Mondet, Pascal Mossuz, Simon Chevalier, and Anne Bertrand

Subjects
0301 basic medicine, Cancer Research, Mitochondrial disease, Cell, HL-60 Cells, Biology, Mitochondrion, 03 medical and health sciences, Oxygen Consumption, 0302 clinical medicine, Mitophagy, Genetics, medicine, Humans, Molecular Biology, Endoplasmic reticulum membrane, Endoplasmic reticulum, Myeloid leukemia, Cell Biology, Hematology, medicine.disease, Mitochondria, Neoplasm Proteins, Cell biology, Repressor Proteins, Leukemia, Myeloid, Acute, 030104 developmental biology, medicine.anatomical_structure, Apoptosis, 030220 oncology & carcinogenesis, Mutation, K562 Cells
Abstract

Mitochondria not only are essential for cell metabolism and energy supply but are also engaged in calcium homeostasis and reactive oxygen species generation and play a key role in apoptosis. As a consequence, functional mitochondrial disorders are involved in many human cancers including acute myeloid leukemia (AML). However, very few data are available on the deregulation of their number and/or shape in leukemic cells, despite the evident link between ultrastructure and function. In this context, we analyzed the ultrastructural mitochondrial parameters (number per cell, mitochondria area, number of cristae/mitochondria, cristal thickness) in five leukemia cell lines (HEL, HL60, K562, KG1, and OCI-AML3) together with the functional assay of their respiratory profile. First, we describe significant differences in basal respiration, maximal respiration, ATP production, and spare respiratory capacity between our cell lines, confirming the various respiratory profiles among leukemia subtypes. Second, we highlight that these variations are obviously associated with significant interleukemia heterogeneity of the number and/or shape of mitochondria. For instance, KG1, characterized by the smallest number of mitochondria together with reduced cristal diameter, had a particularly deficient respiratory profile. In comparison, the HEL and K562 cell lines, both with high respiratory profiles, harbored the largest number of mitochondria/cells with high cristal diameters. Moreover, we report that K562, carrying the ASXL1 mutation, presents significant mitochondria-endoplasmic reticulum deficiency reflected by decreases in the numbers of matrix granules and mitochondria-associated endoplasmic reticulum membrane (MAM) and mitochondrial-derived vesicle (MDV) precursors, which are implicated in the regulatory pathways of cell mortality via the processes of mitophagy and calcium homeostasis. Contrarily, HL60 carried high levels of matrix granules and MAMs and had a higher sensitivity to drugs targeting mitochondria (rotenone/antimycin). We confirm the implication of ASXL1 mutation in this mitochondria dysregulation through the study of transcript expression (from 415 patients with public data) involved in three mitochondrial pathways: (1) endoplasmic reticulum-mitochondria contacts (MAMs), (2) matrix granule homeostasis, and (3) MDV precursor production. Our study offers new and original data on mitochondria structural alterations linked to deregulation of respiration profiles in AMLs and some genetic characteristics, suggesting that modifications of mitochondrial shape and/or number in leukemic cells participate in chemoresistance and could be a targeted mechanism to regulate their proliferative potential.

Published
2020

14. Extracellular vesicles from myelodysplastic mesenchymal stromal cells induce DNA damage and mutagenesis of hematopoietic stem cells through miRNA transfer

Author

Rémy Sadoul, Mathieu Meunier, Karine Laulagnier, Jean-Paul Issartel, Sylvie Tondeur, Sophie Park, Claire Jouzier, Quentin Testard, Audrey Guttin, Christine Lefebvre, Sarah Ancelet, Christine Chatellard, Julien Thevenon, Pierre Hainaut, Virginie Persoons, Benoît Polack, Johanna Zannoni, Jean-François Deleuze, Jean-Yves Cahn, Florent Chuffart, Mylène Pezet, Sophie Rousseaux, David Laurin, Karin Pernet-Gallay, University Clinic of Hematology, Centre Hospitalier Universitaire [Grenoble] (CHU), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Institut de Biologie et Pathologie [CHU Grenoble] (IBP), CHU Grenoble-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes (UGA), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), PDC*line Pharma SAS, Groupe d'imagerie neurofonctionnelle (GIN), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Thérapeutique Recombinante Expérimentale (TIMC-IMAG-TheREx ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), and CHU Grenoble

Subjects
Ribonuclease III, Cancer Research, DNA damage, [SDV]Life Sciences [q-bio], Extracellular vesicles, DEAD-box RNA Helicases, Extracellular Vesicles, microRNA, Humans, Chemistry, Mesenchymal stem cell, Mutagenesis, Mesenchymal Stem Cells, Hematology, Hematopoietic Stem Cells, Microenvironement tumoral, Cell biology, MicroRNAs, Haematopoiesis, Mesenchymal Stem Cell, Oncology, Myelodysplastic Syndromes, Stem cell, Myelodysplastic syndrome, DNA Damage
Abstract

International audience; Physiopathology of myelodysplastic syndrome (MDS) remains poorly understood and the role of the microenvironment is increasingly highlighted. Recent studies in mouse models demonstrate that abnormalities of mesenchymal stromal cells (MSC) contribute to the physiopathology of MDS. In particular, genetic deletion of dicer1, a gene encoding a type III RNase essential for the genesis of miRNA, in murine MSC-derived osteoprogenitors led to a pathological microenvironment generating myelodysplastic features in hematopoietic progenitors and ultimately leading to acute myeloid leukemia [1]. In human, there is an increased susceptibility to senescence of the MDS mesenchymal stem cells and defects in the support properties of the growth of hematopoietic stem cells (HSC) [2]. These observations establish a causal relationship between deregulation of the hematopoietic niche and MDS pathogenesis. However, so far only few studies have addressed the mechanisms by microenvironmental MSC and HSC exchange signals that may interfere with miRNA processing, specifically in the human MDS microenvironment.

Published
2020

15. Long-term follow-up of JAK2 exon 12 polycythemia vera: a French Intergroup of Myeloproliferative Neoplasms (FIM) study

Author

Laurane Cottin, Sylvie Tondeur, Jean-Christophe Ianotto, Olivier Mansier, Lenaïg Le Clech, Jean-Marie Chrétien, Franciane Paul, Mélanie Mercier, Laurent Voillat, Dana Ranta, Benoit de Renzis, Olivier Allangba, François Girodon, Christophe Marzac, Mathilde Hunault-Berger, Valérie Ugo, Corentin Orvain, Driss Chaoui, Jérémie Riou, Eric Lippert, Bruno Cassinat, Jean-Jacques Kiladjian, Suzanne Tavitian, Françoise Boyer, Damien Luque Paz, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut de Biologie et Pathologie [CHU Grenoble] (IBP), CHU Grenoble-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Département d’Hématologie Clinique [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hématologie Clinique [CHI Cornouaille, Quimper], Centre Hospitalier Intercommunal de Cornouaille [Quimper] (CHI Cornouaille [Quimper]), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Fédération Hospitalo-Universitaire 'Grand Ouest Against Leukemia' [Brest] (FHU GOAL), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service d'Hématologie [CH Argenteuil], CH Argenteuil, Hématologie Clinique [CH Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Service d’Hématologie Biologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), 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), Laboratoire d'Hématologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), UFR Santé [UNIV Angers], Université d'Angers (UA), Laboratoire de Biologie Cellulaire [AP-HP Hôpital Saint-Louis], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cellule de Gestion des Données et Evaluation [CHU Angers] (DRCI - CGDE), Service d'hématologie clinique [CHRU de Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service d'Hématologie Clinique [CH Saint-Brieuc], Centre hospitalier Saint-Brieuc, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Centre Hospitalier Chalon-sur-Saône William Morey, Service des maladies du sang [Angers], Service d'hématologie [Angers], Service d'hématologie biologique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris] ((UMR_S1131 / U1131)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Bernardo, Elizabeth, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-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)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
Adult, Male, Cancer Research, Pediatrics, medicine.medical_specialty, Long term follow up, MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cohort Studies, 03 medical and health sciences, Exon, 0302 clinical medicine, Polycythemia vera, [SDV.CAN] Life Sciences [q-bio]/Cancer, Biomarkers, Tumor, medicine, Humans, article clinique, Polycythemia Vera, ComputingMilieux_MISCELLANEOUS, Aged, 030304 developmental biology, 0303 health sciences, Myeloproliferative Disorders, business.industry, Exons, Hematology, Janus Kinase 2, Middle Aged, Prognosis, medicine.disease, Survival Rate, Oncology, Mutation, Female, France, business, Follow-Up Studies, 030215 immunology
Abstract

International audience; No abstract available

Published
2020

16. Expression map of the human exome in CD34+ cells and blood cells: increased alternative splicing in cell motility and immune response genes.

Author

Sylvie Tondeur, Céline Pangault, Tanguy Le Carrour, Yoann Lannay, Rima Benmahdi, Aurélie Cubizolle, Said Assou, Véronique Pantesco, Bernard Klein, Samir Hamamah, Jean-François Schved, Thierry Fest, and John De Vos

Subjects
Medicine, Science
Abstract

BackgroundHematopoietic cells are endowed with very specific biological functions, including cell motility and immune response. These specific functions are dramatically altered during hematopoietic cell differentiation, whereby undifferentiated hematopoietic stem and progenitor cells (HSPC) residing in bone marrow differentiate into platelets, red blood cells and immune cells that exit into the blood stream and eventually move into lymphoid organs or inflamed tissues. The contribution of alternative splicing (AS) to these functions has long been minimized due to incomplete knowledge on AS events in hematopoietic cells.Principal findingsUsing Human Exon ST 1.0 microarrays, the entire exome expression profile of immature CD34+ HSPC and mature whole blood cells was mapped, compared to a collection of solid tissues and made freely available as an online exome expression atlas (Amazonia Exon! : http://amazonia.transcriptome.eu/exon.php). At a whole transcript level, HSPC strongly expressed EREG and the pluripotency marker DPPA4. Using a differential splicing index scheme (dsi), a list of 849 transcripts differentially expressed between hematopoietic cells and solid tissues was computed, that included NEDD9 and CD74. Some of these genes also underwent alternative splicing events during hematopoietic differentiation, such as INPP4B, PTPLA or COMMD6, with varied contribution of CD3+ T cells, CD19+ B cells, CD14+ or CD15+ myelomonocytic populations. Strikingly, these genes were significantly enriched for genes involved in cell motility, cell adhesion, response to wounding and immune processes.ConclusionThe relevance and the precision provided by this exon expression map highlights the contribution of alternative splicing to key feature of blood cells differentiation and function.

Published
2010
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17. Interlaboratory development and validation of a HRM method applied to the detection of JAK2 exon 12 mutations in polycythemia vera patients.

Author

Valerie Ugo, Sylvie Tondeur, Marie-Laurence Menot, Nadine Bonnin, Gerald Le Gac, Carole Tonetti, Veronique Mansat-De Mas, Lydie Lecucq, Jean-Jacques Kiladjian, Christine Chomienne, Christine Dosquet, Nathalie Parquet, Luc Darnige, Marc Porneuf, Martine Escoffre-Barbe, Stephane Giraudier, Eric Delabesse, Bruno Cassinat, and French Intergroup of Myeloproliferative disorders

Subjects
Medicine, Science
Abstract

BACKGROUND: Myeloproliferative disorders are characterized by clonal expansion of normal mature blood cells. Acquired mutations giving rise to constitutive activation of the JAK2 tyrosine kinase has been shown to be present in the majority of patients. Since the demonstration that the V617F mutation in the exon 14 of the JAK2 gene is present in about 90% of patients with Polycythemia Vera (PV), the detection of this mutation has become a key tool for the diagnosis of these patients. More recently, additional mutations in the exon 12 of the JAK2 gene have been described in 5 to 10% of the patients with erythrocytosis. According to the updated WHO criteria the presence of these mutations should be looked for in PV patients with no JAK2 V617F mutation. Reliable and accurate methods dedicated to the detection of these highly variable mutations are therefore necessary. METHODS/FINDINGS: For these reasons we have defined the conditions of a High Resolution DNA Melting curve analysis (HRM) method able to detect JAK2 exon 12 mutations. After having validated that the method was able to detect mutated patients, we have verified that it gave reproducible results in repeated experiments, on DNA extracted from either total blood or purified granulocytes. This HRM assay was further validated using 8 samples bearing different mutant sequences in 4 different laboratories, on 3 different instruments. CONCLUSION: The assay we have developed is thus a valid method, adapted to routine detection of JAK2 exon 12 mutations with highly reproducible results.

Published
2010
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18. Potential Role of OCT4 in Leukemogenesis

Author

Lydia Campos, Sylvie Tondeur, Carmen Mariana Aanei, Emmanuelle Tavernier, Tiphanie Picot, Eric Wattel, Denis Guyotat, Sanae Kesr, Pascale Flandrin-Gresta, and Yuenv Wu

Subjects
0301 basic medicine, Cell cycle checkpoint, Myeloid, Cell, Down-Regulation, Apoptosis, Tretinoin, Biology, Small hairpin RNA, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Cell Line, Tumor, medicine, Humans, Cell Lineage, Clonogenic assay, reproductive and urinary physiology, Cell Proliferation, Genes, Homeobox, Myeloid leukemia, Cell Differentiation, Cell Cycle Checkpoints, Cell Biology, Hematology, Embryonic stem cell, Molecular biology, Leukemia, Myeloid, Acute, Cell Transformation, Neoplastic, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, embryonic structures, Cancer research, Octamer Transcription Factor-3, Developmental Biology
Abstract

Embryonic stem cells typically show properties of long-term self-renewal and lack of differentiation. When appropriately stimulated, they are able to differentiate into all cell lineages, and lose their self-renewal characteristics. These properties are controlled by a series of genes encoding several transcription factors, including OCT4, the product of POU5F1 gene. OCT4 is expressed in germ cell tumors but also aberrantly in cancers developing in differentiated tissues. In a previous study, we observed a high expression of OCT4 in acute myeloid cell lines and primary cells, regardless of the acute myeloid leukemia (AML) subtype. In this study, we investigated the putative oncogenic role of OCT4 in proliferation and differentiation arrest. OCT4 expression was assessed in a panel of myeloid cell lines, together with clonogenic and proliferation properties, before and after differentiation in the presence of retinoic acid (RA). Same experiments were performed under short hairpin RNA (shRNA)-mediated OCT4 inhibition. In the presence of RA, we observed a decrease of OCT4 expression, associated with a loss of clonogenic and proliferation capacities, cell cycle arrest, and upregulation of p21, in HL60, NB4, KASUMI, and Me-1 cell lines. This effect was absent in the KG1a cell line, which did not differentiate. Downregulation of OCT4 by shRNA resulted in the same pattern of differentiation and loss of proliferation. Although KG1a did not differentiate, a decrease in proliferation was observed. Our findings suggest that OCT4 is implicated in the differentiation arrest at least in some types of AML, and that it also plays a role in cell proliferation through different oncogenic mechanisms. OCT4 might be a potential new target for antileukemic treatments.

Published
2017

19. Evaluation by Flow Cytometry of Mature Monocyte Subpopulations for the Diagnosis and Follow-Up of Chronic Myelomonocytic Leukemia

Author

Carmen Mariana Aanei, Sylvie Tondeur, Lydia Campos Catafal, Denis Guyotat, Tiphanie Picot, Pauline Noyel, Emmanuelle Tavernier Tardy, and Pascale Flandrin Gresta

Subjects
0301 basic medicine, Cancer Research, Myeloid, CD14, chronic myelomonocytic leukemia, Chronic myelomonocytic leukemia, monocytic subpopulations, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, Monocytosis, hemic and lymphatic diseases, medicine, Myeloproliferative neoplasm, Original Research, business.industry, Monocyte, flow cytometry, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, karyotype, 030104 developmental biology, medicine.anatomical_structure, Oncology, Dysplasia, 030220 oncology & carcinogenesis, Immunology, next-generation sequencing, Bone marrow, business, peripheral blood monocytosis
Abstract

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm, characterized by persistent monocytosis and dysplasia in at least one myeloid cell lineage. This persistent monocytosis should be distinguished from the reactive monocytosis which is sometimes observed in a context of infections or solid tumors. In 2015, Selimoglu-Buet et al. observed an increased percentage of classical monocytes (CD14+/CD16− >94%) in the peripheral blood (PB) of CMML patients. In this study, using multiparametric flow cytometry (MFC), we assessed the monocytic distribution in PB samples and in bone marrow aspirates from 63 patients with monocytosis or CMML suspicion, and in seven follow-up blood samples from CMML patients treated with hypomethylating agents (HMA). A control group of 12 healthy age-matched donors was evaluated in parallel in order to validate the analysis template. The CMML diagnosis was established in 15 cases in correlation with other clinical manifestations and biological tests. The MFC test for the evaluation of the repartition of monocyte subsets, as previously described by Selimoglu-Buet et al. showed a specificity of 97% in blood and 100% in marrow samples. Additional information regarding the expression of intermediate MO2 monocytes percentage improved the specificity to 100% in blood samples allowing the screening of abnormal monocytosis. The indicative thresholds of CMML monocytosis were different in PB compared to BM samples (classical monocytes >95% for PB and >93% for BM). A decrease of monocyte levels in PB and BM, along with a normalization of monocytes distribution, was observed after treatment in 4/7 CMML patients with favorable evolution. No significant changes were observed in 3/7 patients who did not respond to HMA therapy and also presented unfavorable molecular prognostic factors at diagnosis (ASXL1, TET2, and IDH2 mutations). Considering its simplicity and robustness, the monocyte subsets evaluation by MFC provides relevant information for CMML diagnosis.

Published
2018
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20. Recommendations for accreditation of laboratories in molecular biology of hematologic malignancies

Author

Sylvie Tondeur, Sandrine Hayette, Carole Mauté, Jean-Michel Cayuela, Groupe des biologistes moléculaires des hémopathies malignes, Pascale Flandrin-Gresta, Pascale Cornillet, and Nathalie Gachard

Subjects
Quality Control, Quality Assurance, Health Care, business.industry, Reproducibility of Results, General Medicine, Hematologic Neoplasms, Guideline, Molecular diagnostics, Molecular biology, Accreditation, Internal quality, Laboratory Personnel, Hematological Diseases, Hematological malignancy, Humans, Medicine, France, Laboratories, business, Molecular Biology, Quality assurance
Abstract

Over recent years, the development of molecular biology techniques has improved the hematological diseases diagnostic and follow-up. Consequently, these techniques are largely used in the biological screening of these diseases; therefore the Hemato-oncology molecular diagnostics laboratories must be actively involved in the accreditation process according the ISO 15189 standard. The French group of molecular biologists (GBMHM) provides requirements for the implementation of quality assurance for the medical molecular laboratories. This guideline states the recommendations for the pre-analytical, analytical (methods validation procedures, quality controls, reagents), and post-analytical conditions. In addition, herein we state a strategy for the internal quality control management. These recommendations will be regularly updated.

Published
2015

21. Expression of embryonic stem cell markers in acute myeloid leukemia

Author

Pascale Flandrin-Gresta, Carmen Mariana Aanei, Marina Gouttenoire, Denis Guyotat, Tiphanie Picot, Sylvie Tondeur, Amandine Fayard, Lydia Campos, Eric Wattel, and Emmanuelle Tavernier-Tardy

Subjects
0301 basic medicine, Adult, Male, Lineage (genetic), Lewis X Antigen, Antigens, CD34, Bone Marrow Cells, Biology, Immunophenotyping, 03 medical and health sciences, Cancer stem cell, Biomarkers, Tumor, Humans, Embryonic Stem Cells, RC254-282, Aged, SOXB1 Transcription Factors, Myeloid leukemia, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cell Differentiation, General Medicine, Middle Aged, Flow Cytometry, Fucosyltransferases, Hematopoietic Stem Cells, Prognosis, Embryonic stem cell, ADP-ribosyl Cyclase 1, Gene Expression Regulation, Neoplastic, Haematopoiesis, Leukemia, Myeloid, Acute, 030104 developmental biology, embryonic structures, Cancer research, Female, Stem cell, Octamer Transcription Factor-3
Abstract

Acute myeloid leukemia is driven by leukemic stem cells which can be identified by cross lineage expression or arrest of differentiation compared to normal hematopoietic stem cells. Self-renewal and lack of differentiation are also features of stem cells and have been associated with the expression of embryonic genes. The aim of our study was to evaluate the expression of embryonic antigens (OCT4, NANOG, SOX2, SSEA1, SSEA3) in hematopoietic stem cell subsets (CD34+CD38− and CD34+CD38+) from normal bone marrows and in samples from acute myeloid leukemia patients. We observed an upregulation of the transcription factors OCT4 and SOX2 in leukemic cells as compared to normal cells. Conversely, SSEA1 protein was downregulated in leukemic cells. The expression of OCT4, SOX2, and SSEA3 was higher in CD34+CD38− than in CD34+CD38+ subsets in leukemic cells. There was no correlation with biological characteristics of the leukemia. We evaluated the prognostic value of marker expression in 69 patients who received an intensive treatment. The rate of complete remission was not influenced by the level of expression of markers. Overall survival was significantly better for patients with high SOX2 levels, which was unexpected because of the inverse correlation with favorable genetic subtypes. These results prompt us to evaluate the potential role of these markers in leukemogenesis and to test their relevance for better leukemic stem cell identification.

Published
2017

22. Absence of CALR mutations in JAK2-negative polycythemia

Author

Olivier Nibourel, Eric Lippert, Olivier Mansier, Franciane Paul, Damien Luque Paz, Sylvie Tondeur, Claude Preudhomme, Aurélie Chauveau, Mathieu Wemeau, and Valérie Ugo

Subjects
Male, Lineage (genetic), medicine.disease_cause, Cohort Studies, 03 medical and health sciences, Exon, 0302 clinical medicine, Polycythemia vera, hemic and lymphatic diseases, Increased Hematopoiesis, medicine, Humans, Online Only Articles, Polycythemia Vera, Myeloproliferative neoplasm, Genetics, Mutation, Janus kinase 2, biology, food and beverages, Hematology, Janus Kinase 2, medicine.disease, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Female, Calreticulin, 030215 immunology
Abstract

Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) responsible for increased hematopoiesis, mainly affecting the erythroid lineage. The diagnosis of PV has been simplified enormously by the description of JAK2 mutations, affecting the canonical V617 in exon 14 in more than 95% of cases

Published
2016

23. Use of hematopoietic progenitor cell count on the Sysmex XE-2100 for peripheral blood stem cell harvest monitoring

Author

Véronique Baccini, Loïc Garçon, Christophe Marzac, Liliane Dal Cortivo, Florence Ajchenbaum-Cymbalista, Sylvie Tondeur, Françoise Audat, Françoise Valensi, Rémi Letestu, François Lefrère, Ramdane Belhocine, and Jean-Yves Perrot

Subjects
Cancer Research, Sysmex XE-2100, medicine.diagnostic_test, business.industry, Cell, CD34, Antigens, CD34, Hematology, Hematopoietic Stem Cells, Sensitivity and Specificity, Blood Cell Count, Flow cytometry, Andrology, Apheresis, medicine.anatomical_structure, Hematopoietic progenitor, Oncology, Immunology, Tissue and Organ Harvesting, medicine, Enumeration, Humans, Stem cell, business
Abstract

Successful peripheral blood stem cell (PBSC) collection depends on the timing of apheresis based on CD34+ cell enumeration. Because this analysis is expensive and induces organization difficulties, we evaluated hematopoietic progenitor cell (HPC) quantification on the Sysmex XE-2100 as a surrogate analysis. We tested 157 blood samples for CD34+ cells and HPC counts. We found a good linear correlation between HPC and CD34+ and determined simple rules allowing to use HPC count in daily practice. We set a positive cut-off30 HPC/mm(3) for allowing PBSC harvest and a negative cut-off at 0 HPC/mm(3) for which collection should be delayed. These two situations accounted for 62% of cases and CD34+ cell count by flow cytometry confirmed HPC result in 95% of cases. Between 0 and 30 HPC/mm3, CD34+ enumeration is required for decision-making. We conclude that HPC count may be a useful surrogate for CD34+ enumeration in PBSC harvest monitoring.

Published
2007

24. Overcoming bacterial DNA contamination in real-time PCR and RT-PCR reactions for LacZ detection in cell therapy monitoring

Author

Jane-Lise Samuel, Sylvie Tondeur, Denise Paulin, Onnik Agbulut, Bruno Cassinat, M L Menot, Philippe Menasché, Christine Chomienne, and Jérôme Larghero

Subjects
DNA, Bacterial, Cell Transplantation, Bone Marrow Cells, Mice, Transgenic, Biology, Polymerase Chain Reaction, law.invention, Microbiology, Mice, chemistry.chemical_compound, Genes, Reporter, law, Primer dimer, Animals, Deoxyribonuclease I, Taq Polymerase, Molecular Biology, Polymerase chain reaction, Reverse Transcriptase Polymerase Chain Reaction, Multiple displacement amplification, Genetic Therapy, Cell Biology, Molecular biology, Reverse transcription polymerase chain reaction, Real-time polymerase chain reaction, Lac Operon, chemistry, DNA Contamination, Applications of PCR, Taq polymerase
Abstract

Since the introduction of the polymerase chain reaction the presence of contaminating bacterial DNA in the Taq polymerase preparations has hampered the use of this technique in microbiology. Lately, this inconvenience has equally impeded gene quantification in the field of cell or gene therapy, where bacterial genes such as LacZ are often used as tags to detect vectors or cells after their injection in the recipient organism. Several means to overcome the DNA contamination of Taq Polymerase have been reported with variable degrees of decontamination efficiency and alteration of the PCR reaction. Here we propose two protocols to efficiently quantify DNA or RNA from the LacZ gene by real-time PCR using either decontamination by low concentrations of DNAse I prior to PCR amplification or a highly purified Taq Polymerase which is devoid of detectable contamination.

Published
2004

25. The MLL recombinome of acute leukemias in 2013

Author

E. Launay, Vesa Juvonen, Julia Hofmann, Emmanuelle Clappier, T S Park, M.M. van den Heuvel-Eibrink, Anja Möricke, S. Kubetzko, V H J van der Velden, Aline Renneville, Eric Delabesse, William W.L. Choi, Paula Gameiro, Jean Michel Cayuela, L Fechina, Jong Rak Choi, Cristina N. Alonso, Theodor Dingermann, Clara Bueno, U. Zur Stadt, P. Archer, Martin Stanulla, Mary Callanan, Manuel R. Teixeira, Catherine Henry, Marie Jarošová, Nuno Cerveira, Daniela Gröger, M. De Braekeleer, Thomas Burmeister, H. Lapillone, Rosemary Sutton, G te Kronnie, K. Mass-Malo, J J M van Dongen, Jeremy Hancock, Cornelia Eckert, E De Braekeleer, Olga V. Aleinikova, Mara Silva, Sylvie Tondeur, Tomasz Szczepański, Renata Binato, Christian M. Zwaan, Martin Schrappe, Claus Meyer, Eric Lippert, P. M. Kakadiya, Paola Ballerini, Martina Ahlmann, Renate Panzer-Grümayer, Hélène Cavé, Michael Dworzak, Lukasz Sedek, S. Wehner, Dongsoon Lee, Josef Vormoor, Olaf Heidenreich, A. Kolenova, Shai Izraeli, Pascaline Talmant, Elizabeth Macintyre, Charles Herbaux, AM Kustanovich, Stefan K. Bohlander, Jan Trka, Grigory Tsaur, N. C. Venn, Luba Trakhtenbrot, Thomas Klingebiel, Pablo Menendez, T Lund-Aho, Mariana Emerenciano, Pascale Cornillet-Lefebvre, Juergen Krauter, Sabine Strehl, Beat W. Schäfer, M. Pombo De Oliveira, Marian H. Harris, H. O. Madsen, Patrick Villarese, Eva A. Coenen, Jan Zuna, L Lo Nigro, Giovanni Cazzaniga, S H Oh, Rolf Marschalek, Immunology, Pediatrics, Meyer, C, Hofmann, J, Burmeister, T, Gröger, D, Park, T, Emerenciano, M, Pombo de Oliveira, M, Renneville, A, Villarese, P, Macintyre, E, Cavé, H, Clappier, E, Mass-Malo, K, Zuna, J, Trka, J, De Braekeleer, E, De Braekeleer, M, Oh, S, Tsaur, G, Fechina, L, van der Velden, V, van Dongen, J, Delabesse, E, Binato, R, Silva, M, Kustanovich, A, Aleinikova, O, Harris, M, Lund-Aho, T, Juvonen, V, Heidenreich, O, Vormoor, J, Choi, W, Jarosova, M, Kolenova, A, Bueno, C, Menendez, P, Wehner, S, Eckert, C, Talmant, P, Tondeur, S, Lippert, E, Launay, E, Henry, C, Ballerini, P, Lapillone, H, Callanan, M, Cayuela, J, Herbaux, C, Cazzaniga, G, Kakadiya, P, Bohlander, S, Ahlmann, M, Choi, J, Gameiro, P, Lee, D, Krauter, J, Cornillet-Lefebvre, P, Te Kronnie, G, Schäfer, B, Kubetzko, S, Alonso, C, zur Stadt, U, Sutton, R, Venn, N, Izraeli, S, Trakhtenbrot, L, Madsen, H, Archer, P, Hancock, J, Cerveira, N, Teixeira, M, Lo Nigro, L, Möricke, A, Stanulla, M, Schrappe, M, Sedék, L, Szczepański, T, Zwaan, C, Coenen, E, van den Heuvel-Eibrink, M, Strehl, S, Dworzak, M, Panzer-Grümayer, R, Dingermann, T, Klingebiel, T, and Marschalek, R

Subjects
MLL, Male, Cancer Research, Oncogene Proteins, Fusion, Polymerase Chain Reaction, Translocation, Genetic, chromosomal translocations, Mice, 0302 clinical medicine, AML, hemic and lymphatic diseases, Age Factor, acute leukemia, Child, Genetics, Aged, 80 and over, Gene Rearrangement, 0303 health sciences, Acute leukemia, Leukemia, biology, Age Factors, Chromosome Breakage, Hematology, Middle Aged, Prognosis, 3. Good health, translocation partner genes, KMT2A, Oncology, 030220 oncology & carcinogenesis, Child, Preschool, Acute Disease, Myeloid-Lymphoid Leukemia Protein, Original Article, Female, Chromosome breakage, Human, Adult, Adolescent, Prognosi, Chromosomal rearrangement, ta3111, 03 medical and health sciences, Young Adult, medicine, Animals, Humans, neoplasms, 030304 developmental biology, Aged, Animal, Breakpoint, Infant, Newborn, Infant, Gene rearrangement, Histone-Lysine N-Methyltransferase, medicine.disease, ta3122, biology.protein, ALL
Abstract

Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (≈ 90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.

Published
2013

26. E4F1 deficiency results in oxidative stress-mediated cell death of leukemic cells

Author

Chantal Jacquet, Pierre Dubus, Geneviève Rodier, Emilie Schrepfer, Gwendaline Lledo, Laetitia K. Linares, Matthieu Lacroix, Olivier Kirsh, Sylviane Lagarrigue, Julie Caramel, Laurent Le Cam, Sylvie Tondeur, Claude Sardet, Elodie Hatchi, Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Montpellier 1 ( UM1 ), Institut de recherche en cancérologie de Montpellier ( IRCM ), Université Montpellier 1 ( UM1 ) -CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Département d'hématologie biologique[Montpellier], Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -CHU Saint-Eloi, Histologie et Pathologie Moléculaire des Tumeurs, Université Bordeaux Segalen - Bordeaux 2-EA 2406, Agence Nationale pour la Recherche (ANR),the Association pour la lutte contre le Cancer (ARC), the Leukemia Program from the Fondation de France, the British AICR foundation, by la Fondation pour la Recherche Médicale (CS équipe labelisée 2007) and the institutional supports of the INSERM Avenir Program (LLC) and the CNRS (CS). EH and JC are supported by an ARC PhD and AICR post-doctoral fellowships, respectively., Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université Montpellier 1 (UM1), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, and Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
Myeloid, Cell, Mitochondrion, medicine.disease_cause, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, leukemic cells, 0302 clinical medicine, hemic and lymphatic diseases, Immunology and Allergy, oxidative stress, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, RNA, Small Interfering, Mice, Knockout, 0303 health sciences, Myeloid leukemia, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, 3. Good health, DNA-Binding Proteins, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Cell Transformation, Neoplastic, cell death, Mice, Inbred DBA, 030220 oncology & carcinogenesis, Signal transduction, Signal Transduction, Programmed cell death, Mice, 129 Strain, Ubiquitin-Protein Ligases, Immunology, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Article, histiocytic sarcoma, 03 medical and health sciences, Cell Line, Tumor, medicine, Autophagy, Animals, Humans, 030304 developmental biology, knock-out, [SDV.GEN]Life Sciences [q-bio]/Genetics, Base Sequence, Macrophages, Molecular biology, Mice, Inbred C57BL, Repressor Proteins, E4F1, Cell culture, Cancer research, Carcinogenesis, Reactive Oxygen Species, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Transcription Factors
Abstract

Deletion of E4F1 inflicts mitochondrial damage and oxidative stress on murine and human myeloid leukemia cells but not healthy macrophages., The multifunctional E4F1 protein was originally discovered as a target of the E1A viral oncoprotein. Growing evidence indicates that E4F1 is involved in key signaling pathways commonly deregulated during cell transformation. In this study, we investigate the influence of E4F1 on tumorigenesis. Wild-type mice injected with fetal liver cells from mice lacking CDKN2A, the gene encoding Ink4a/Arf, developed histiocytic sarcomas (HSs), a tumor originating from the monocytic/macrophagic lineage. Cre-mediated deletion of E4F1 resulted in the death of HS cells and tumor regression in vivo and extended the lifespan of recipient animals. In murine and human HS cell lines, E4F1 inactivation resulted in mitochondrial defects and increased production of reactive oxygen species (ROS) that triggered massive cell death. Notably, these defects of E4F1 depletion were observed in HS cells but not healthy primary macrophages. Short hairpin RNA–mediated depletion of E4F1 induced mitochondrial defects and ROS-mediated death in several human myeloid leukemia cell lines. E4F1 protein is overexpressed in a large subset of human acute myeloid leukemia samples. Together, these data reveal a role for E4F1 in the survival of myeloid leukemic cells and support the notion that targeting E4F1 activities might have therapeutic interest.

Published
2011

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