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36 results on '"M'Boyba Diop"'

1. A miR-150/TET3 pathway regulates the generation of mouse and human non-classical monocyte subset

Author

Dorothée Selimoglu-Buet, Julie Rivière, Hussein Ghamlouch, Laura Bencheikh, Catherine Lacout, Margot Morabito, M’boyba Diop, Guillaume Meurice, Marie Breckler, Aurélie Chauveau, Camille Debord, Franck Debeurme, Raphael Itzykson, Nicolas Chapuis, Christophe Willekens, Orianne Wagner-Ballon, Olivier A. Bernard, Nathalie Droin, and Eric Solary

Subjects
Science
Abstract

A decrease in the fraction of non-classical monocytes is a hallmark of chronic myelomonocytic leukaemia. Taking advantage of this abnormal situation, the authors identify a mechanistic link between miR-150 and TET3 as being involved in monocyte subset generation.

Published
2018
Full Text
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3. 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

4. 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

5. Supplementary Figures and Legends from Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene–Driven Myeloid Leukemia

Author

Thomas Mercher, Juerg Schwaller, Françoise Pflumio, Arnaud Petit, Berthold Göttgens, Olivier A. Bernard, Isabelle Godin, Camille Lobry, Nathalie Droin, Claus Nerlov, Sébastien Malinge, Franco Locatelli, Riccardo Masetti, Muriel Gaudry, William Vainchenker, Antoine H.F.M. Peters, Eric Delabesse, Jean Luc Villeval, Loélia Babin, Erika Brunet, Yann Lecluse, Bastien Job, M'Boyba Diop, Sarah J. Kinston, Marie-Laure Arcangeli, Alexandre Fagnan, Cécile Thirant, Fabien Boudia, Hélène Lapillonne, Chrystèle Bilhou-Nabera, Paola Ballerini, Zakia Aid, Elie Robert, Vaia Stavropoulou, Esteve Noguera, and Cécile K. Lopez

Abstract

Supplementary Figures and Legends

Published
2023

6. Data from Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene–Driven Myeloid Leukemia

Author

Thomas Mercher, Juerg Schwaller, Françoise Pflumio, Arnaud Petit, Berthold Göttgens, Olivier A. Bernard, Isabelle Godin, Camille Lobry, Nathalie Droin, Claus Nerlov, Sébastien Malinge, Franco Locatelli, Riccardo Masetti, Muriel Gaudry, William Vainchenker, Antoine H.F.M. Peters, Eric Delabesse, Jean Luc Villeval, Loélia Babin, Erika Brunet, Yann Lecluse, Bastien Job, M'Boyba Diop, Sarah J. Kinston, Marie-Laure Arcangeli, Alexandre Fagnan, Cécile Thirant, Fabien Boudia, Hélène Lapillonne, Chrystèle Bilhou-Nabera, Paola Ballerini, Zakia Aid, Elie Robert, Vaia Stavropoulou, Esteve Noguera, and Cécile K. Lopez

Abstract

Fusion oncogenes are prevalent in several pediatric cancers, yet little is known about the specific associations between age and phenotype. We observed that fusion oncogenes, such as ETO2–GLIS2, are associated with acute megakaryoblastic or other myeloid leukemia subtypes in an age-dependent manner. Analysis of a novel inducible transgenic mouse model showed that ETO2–GLIS2 expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in adult bone marrow hematopoietic stem cells resulted in a shift toward myeloid transformation with a strikingly delayed in vivo leukemogenic potential. Chromatin accessibility and single-cell transcriptome analyses indicate ontogeny-dependent intrinsic and ETO2–GLIS2-induced differences in the activities of key transcription factors, including ERG, SPI1, GATA1, and CEBPA. Importantly, switching off the fusion oncogene restored terminal differentiation of the leukemic blasts. Together, these data show that aggressiveness and phenotypes in pediatric acute myeloid leukemia result from an ontogeny-related differential susceptibility to transformation by fusion oncogenes.Significance:This work demonstrates that the clinical phenotype of pediatric acute myeloid leukemia is determined by ontogeny-dependent susceptibility for transformation by oncogenic fusion genes. The phenotype is maintained by potentially reversible alteration of key transcription factors, indicating that targeting of the fusions may overcome the differentiation blockage and revert the leukemic state.See related commentary by Cruz Hernandez and Vyas, p. 1653.This article is highlighted in the In This Issue feature, p. 1631

Published
2023

7. Supplementary Tables 1 to 11 from Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene–Driven Myeloid Leukemia

Author

Thomas Mercher, Juerg Schwaller, Françoise Pflumio, Arnaud Petit, Berthold Göttgens, Olivier A. Bernard, Isabelle Godin, Camille Lobry, Nathalie Droin, Claus Nerlov, Sébastien Malinge, Franco Locatelli, Riccardo Masetti, Muriel Gaudry, William Vainchenker, Antoine H.F.M. Peters, Eric Delabesse, Jean Luc Villeval, Loélia Babin, Erika Brunet, Yann Lecluse, Bastien Job, M'Boyba Diop, Sarah J. Kinston, Marie-Laure Arcangeli, Alexandre Fagnan, Cécile Thirant, Fabien Boudia, Hélène Lapillonne, Chrystèle Bilhou-Nabera, Paola Ballerini, Zakia Aid, Elie Robert, Vaia Stavropoulou, Esteve Noguera, and Cécile K. Lopez

Abstract

Supplementary Tables 1 to 11

Published
2023

8. Supplementary Data from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Sebastien Malinge, Thomas Mercher, Eric Delabesse, Jean-Pierre Bourquin, Paola Ballerini, Birgit Geoerger, Rishi S. Kotecha, Carole Barin Bonnigal, Elizabeth Macintyre, Olivier A. Bernard, Muriel Gaudry, John D. Crispino, Laurence C. Cheung, Beat C. Bornhauser, Nathalie Droin, Yann Lecluse, Estelle Daudigeos, Gaelle Pierron, Damien Plassard, Stephanie Lagarde, Nais Prade, Zakia Aid, Damien Roos-Weil, Yi-Chien Tsai, Silvia Jenni, M'Boyba Diop, Kunjal Panchal, Cathy Ignacimouttou, Aurélie Siret, and Anouchka P. Laurent

Abstract

Material and Methods, Figure legends

Published
2023

9. Figure S5 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Sebastien Malinge, Thomas Mercher, Eric Delabesse, Jean-Pierre Bourquin, Paola Ballerini, Birgit Geoerger, Rishi S. Kotecha, Carole Barin Bonnigal, Elizabeth Macintyre, Olivier A. Bernard, Muriel Gaudry, John D. Crispino, Laurence C. Cheung, Beat C. Bornhauser, Nathalie Droin, Yann Lecluse, Estelle Daudigeos, Gaelle Pierron, Damien Plassard, Stephanie Lagarde, Nais Prade, Zakia Aid, Damien Roos-Weil, Yi-Chien Tsai, Silvia Jenni, M'Boyba Diop, Kunjal Panchal, Cathy Ignacimouttou, Aurélie Siret, and Anouchka P. Laurent

Abstract

Phenotypic, transcriptomic and genetic validation of PDX models

Published
2023

10. Supplementary Table 3 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Sebastien Malinge, Thomas Mercher, Eric Delabesse, Jean-Pierre Bourquin, Paola Ballerini, Birgit Geoerger, Rishi S. Kotecha, Carole Barin Bonnigal, Elizabeth Macintyre, Olivier A. Bernard, Muriel Gaudry, John D. Crispino, Laurence C. Cheung, Beat C. Bornhauser, Nathalie Droin, Yann Lecluse, Estelle Daudigeos, Gaelle Pierron, Damien Plassard, Stephanie Lagarde, Nais Prade, Zakia Aid, Damien Roos-Weil, Yi-Chien Tsai, Silvia Jenni, M'Boyba Diop, Kunjal Panchal, Cathy Ignacimouttou, Aurélie Siret, and Anouchka P. Laurent

Abstract

List of the SNVs identified through RNA-sequencing

Published
2023

11. Supplementary Table 7 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Sebastien Malinge, Thomas Mercher, Eric Delabesse, Jean-Pierre Bourquin, Paola Ballerini, Birgit Geoerger, Rishi S. Kotecha, Carole Barin Bonnigal, Elizabeth Macintyre, Olivier A. Bernard, Muriel Gaudry, John D. Crispino, Laurence C. Cheung, Beat C. Bornhauser, Nathalie Droin, Yann Lecluse, Estelle Daudigeos, Gaelle Pierron, Damien Plassard, Stephanie Lagarde, Nais Prade, Zakia Aid, Damien Roos-Weil, Yi-Chien Tsai, Silvia Jenni, M'Boyba Diop, Kunjal Panchal, Cathy Ignacimouttou, Aurélie Siret, and Anouchka P. Laurent

Abstract

Differentially expressed genes in the human B-ALL cohort

Published
2023

12. Supplementary Table 1 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Sebastien Malinge, Thomas Mercher, Eric Delabesse, Jean-Pierre Bourquin, Paola Ballerini, Birgit Geoerger, Rishi S. Kotecha, Carole Barin Bonnigal, Elizabeth Macintyre, Olivier A. Bernard, Muriel Gaudry, John D. Crispino, Laurence C. Cheung, Beat C. Bornhauser, Nathalie Droin, Yann Lecluse, Estelle Daudigeos, Gaelle Pierron, Damien Plassard, Stephanie Lagarde, Nais Prade, Zakia Aid, Damien Roos-Weil, Yi-Chien Tsai, Silvia Jenni, M'Boyba Diop, Kunjal Panchal, Cathy Ignacimouttou, Aurélie Siret, and Anouchka P. Laurent

Abstract

Characteristics of the B-ALL cohort

Published
2023

13. Supplementary Table 8 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Sebastien Malinge, Thomas Mercher, Eric Delabesse, Jean-Pierre Bourquin, Paola Ballerini, Birgit Geoerger, Rishi S. Kotecha, Carole Barin Bonnigal, Elizabeth Macintyre, Olivier A. Bernard, Muriel Gaudry, John D. Crispino, Laurence C. Cheung, Beat C. Bornhauser, Nathalie Droin, Yann Lecluse, Estelle Daudigeos, Gaelle Pierron, Damien Plassard, Stephanie Lagarde, Nais Prade, Zakia Aid, Damien Roos-Weil, Yi-Chien Tsai, Silvia Jenni, M'Boyba Diop, Kunjal Panchal, Cathy Ignacimouttou, Aurélie Siret, and Anouchka P. Laurent

Abstract

Reagents and Resources

Published
2023

14. Data from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Sebastien Malinge, Thomas Mercher, Eric Delabesse, Jean-Pierre Bourquin, Paola Ballerini, Birgit Geoerger, Rishi S. Kotecha, Carole Barin Bonnigal, Elizabeth Macintyre, Olivier A. Bernard, Muriel Gaudry, John D. Crispino, Laurence C. Cheung, Beat C. Bornhauser, Nathalie Droin, Yann Lecluse, Estelle Daudigeos, Gaelle Pierron, Damien Plassard, Stephanie Lagarde, Nais Prade, Zakia Aid, Damien Roos-Weil, Yi-Chien Tsai, Silvia Jenni, M'Boyba Diop, Kunjal Panchal, Cathy Ignacimouttou, Aurélie Siret, and Anouchka P. Laurent

Abstract

Purpose:Children with Down syndrome (constitutive trisomy 21) that develop acute lymphoblastic leukemia (DS-ALL) have a 3-fold increased likelihood of treatment-related mortality coupled with a higher cumulative incidence of relapse, compared with other children with B-cell acute lymphoblastic leukemia (B-ALL). This highlights the lack of suitable treatment for Down syndrome children with B-ALL.Experimental Design:To facilitate the translation of new therapeutic agents into clinical trials, we built the first preclinical cohort of patient-derived xenograft (PDX) models of DS-ALL, comprehensively characterized at the genetic and transcriptomic levels, and have proven its suitability for preclinical studies by assessing the efficacy of drug combination between the MEK inhibitor trametinib and conventional chemotherapy agents.Results:Whole-exome and RNA-sequencing experiments revealed a high incidence of somatic alterations leading to RAS/MAPK pathway activation in our cohort of DS-ALL, as well as in other pediatric B-ALL presenting somatic gain of the chromosome 21 (B-ALL+21). In murine and human B-cell precursors, activated KRASG12D functionally cooperates with trisomy 21 to deregulate transcriptional networks that promote increased proliferation and self renewal, as well as B-cell differentiation blockade. Moreover, we revealed that inhibition of RAS/MAPK pathway activation using the MEK1/2 inhibitor trametinib decreased leukemia burden in several PDX models of B-ALL+21, and enhanced survival of DS-ALL PDX in combination with conventional chemotherapy agents such as vincristine.Conclusions:Altogether, using novel and suitable PDX models, this study indicates that RAS/MAPK pathway inhibition represents a promising strategy to improve the outcome of Down syndrome children with B-cell precursor leukemia.

Published
2023

15. Supplementary Table 2 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Sebastien Malinge, Thomas Mercher, Eric Delabesse, Jean-Pierre Bourquin, Paola Ballerini, Birgit Geoerger, Rishi S. Kotecha, Carole Barin Bonnigal, Elizabeth Macintyre, Olivier A. Bernard, Muriel Gaudry, John D. Crispino, Laurence C. Cheung, Beat C. Bornhauser, Nathalie Droin, Yann Lecluse, Estelle Daudigeos, Gaelle Pierron, Damien Plassard, Stephanie Lagarde, Nais Prade, Zakia Aid, Damien Roos-Weil, Yi-Chien Tsai, Silvia Jenni, M'Boyba Diop, Kunjal Panchal, Cathy Ignacimouttou, Aurélie Siret, and Anouchka P. Laurent

Abstract

List of the SNVs identified through whole exome sequencing

Published
2023

16. Supplementary Table 4 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Sebastien Malinge, Thomas Mercher, Eric Delabesse, Jean-Pierre Bourquin, Paola Ballerini, Birgit Geoerger, Rishi S. Kotecha, Carole Barin Bonnigal, Elizabeth Macintyre, Olivier A. Bernard, Muriel Gaudry, John D. Crispino, Laurence C. Cheung, Beat C. Bornhauser, Nathalie Droin, Yann Lecluse, Estelle Daudigeos, Gaelle Pierron, Damien Plassard, Stephanie Lagarde, Nais Prade, Zakia Aid, Damien Roos-Weil, Yi-Chien Tsai, Silvia Jenni, M'Boyba Diop, Kunjal Panchal, Cathy Ignacimouttou, Aurélie Siret, and Anouchka P. Laurent

Abstract

List of fusion transcripts identified through RNA-sequencing

Published
2023

17. Supplementary Table 6 from Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Sebastien Malinge, Thomas Mercher, Eric Delabesse, Jean-Pierre Bourquin, Paola Ballerini, Birgit Geoerger, Rishi S. Kotecha, Carole Barin Bonnigal, Elizabeth Macintyre, Olivier A. Bernard, Muriel Gaudry, John D. Crispino, Laurence C. Cheung, Beat C. Bornhauser, Nathalie Droin, Yann Lecluse, Estelle Daudigeos, Gaelle Pierron, Damien Plassard, Stephanie Lagarde, Nais Prade, Zakia Aid, Damien Roos-Weil, Yi-Chien Tsai, Silvia Jenni, M'Boyba Diop, Kunjal Panchal, Cathy Ignacimouttou, Aurélie Siret, and Anouchka P. Laurent

Abstract

List of datasets enriched in murine B cell precursors (GSEA analyses)

Published
2023

18. HDAC1 and PRC2 mediate combinatorial control in SPI1/PU.1-dependent gene repression in murine erythroleukaemia

Author

Sebastian Gregoricchio, Lélia Polit, Michela Esposito, Jérémy Berthelet, Laure Delestré, Emilie Evanno, M’Boyba Diop, Isabelle Gallais, Hanna Aleth, Mathilde Poplineau, Wilbert Zwart, Frank Rosenbauer, Fernando Rodrigues-Lima, Estelle Duprez, Valentina Boeva, Christel Guillouf, 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, Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), 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), Department of Computer Science [ETH Zürich] (D-INFK), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), GUILLOUF, Christel, Institut Gustave Roussy (IGR), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), and ANR-11-LABX-0071,WHO AM I,Determinants de l'Identité : de la molécule à l'individu(2011)

Subjects
[SDV]Life Sciences [q-bio], Polycomb Repressive Complex 2, Acetylation, Histone Deacetylase 1, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Chromatin and Epigenetics, Chromatin, [SDV] Life Sciences [q-bio], Mice, Proto-Oncogene Proteins, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Trans-Activators, Animals, Gene Regulation, Leukemia, Erythroblastic, Acute, Promoter Regions, Genetic
Abstract

Although originally described as transcriptional activator, SPI1/PU.1, a major player in haematopoiesis whose alterations are associated with haematological malignancies, has the ability to repress transcription. Here, we investigated the mechanisms underlying gene repression in the erythroid lineage, in which SPI1 exerts an oncogenic function by blocking differentiation. We show that SPI1 represses genes by binding active enhancers that are located in intergenic or gene body regions. HDAC1 acts as a cooperative mediator of SPI1-induced transcriptional repression by deacetylating SPI1-bound enhancers in a subset of genes, including those involved in erythroid differentiation. Enhancer deacetylation impacts on promoter acetylation, chromatin accessibility and RNA pol II occupancy. In addition to the activities of HDAC1, polycomb repressive complex 2 (PRC2) reinforces gene repression by depositing H3K27me3 at promoter sequences when SPI1 is located at enhancer sequences. Moreover, our study identified a synergistic relationship between PRC2 and HDAC1 complexes in mediating the transcriptional repression activity of SPI1, ultimately inducing synergistic adverse effects on leukaemic cell survival. Our results highlight the importance of the mechanism underlying transcriptional repression in leukemic cells, involving complex functional connections between SPI1 and the epigenetic regulators PRC2 and HDAC1., Nucleic Acids Research, 50 (14), ISSN:1362-4962, ISSN:0301-5610

Published
2022

19. 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

20. Biology and prognostic impact of clonal plasmacytoid dendritic cells in chronic myelomonocytic leukemia

Author

Mrinal M. Patnaik, Pierre Fenaux, Christophe Willekens, Philippe Rameau, Floriane Noel, Raphael Itzykson, Matthieu Duchmann, Nolwenn Lucas, Eric Solary, Paula Michea, M'Boyba Diop, Matthew T. Howard, Sandrine Niyongere, Rebecca L. King, Eric Padron, Vassili Soumelis, Michaela Fontenay, Martin E. Fernandez-Zapico, Gérard Pierron, Véronique Saada, Nathalie Droin, Vincent Ribrag, and Olivier Kosmider

Subjects
Male, 0301 basic medicine, Cancer Research, Regulatory T cell, CD34, Chronic myelomonocytic leukemia, Biology, T-Lymphocytes, Regulatory, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, Antigens, CD, Bone Marrow, medicine, Humans, Aged, Aged, 80 and over, Acute leukemia, medicine.diagnostic_test, Cluster of differentiation, Membrane Proteins, Leukemia, Myelomonocytic, Chronic, hemic and immune systems, Dendritic Cells, Hematology, Prognosis, medicine.disease, Leukemia, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, Female, Bone marrow, Biomarkers
Abstract

Islands of CD123high cells have been commonly described in the bone marrow of patients with chronic myelomonocytic leukemia (CMML). Using a multiparameter flow cytometry assay, we detected an excess of CD123+ mononucleated cells that are lineage-negative, CD45+, CD11c−, CD33−, HLA-DR+, BDCA-2+, BDCA-4+ in the bone marrow of 32/159 (20%) patients. Conventional and electron microscopy, flow cytometry detection of cell surface markers, gene expression analyses, and the ability to synthesize interferon alpha in response to Toll-like receptor agonists identified these cells as bona fide plasmacytoid dendritic cells (pDCs). Whole-exome sequencing of sorted monocytes and pDCs identified somatic mutations in genes of the oncogenic RAS pathway in the two cell types of every patient. CD34+ cells could generate high amount of pDCs in the absence of FMS-like tyrosine kinase 3-ligand (FLT3L). Finally, an excess of pDCs correlates with regulatory T cell accumulation and an increased risk of acute leukemia transformation. These results demonstrate the FLT3L-independent accumulation of clonal pDCs in the bone marrow of CMML patients with mutations affecting the RAS pathway, which is associated with a higher risk of disease progression.

Published
2019

21. Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia

Author

Damien Plassard, Estelle Daudigeos, Elizabeth Macintyre, Kunjal Panchal, Yann Lécluse, Stéphanie Lagarde, Anouchka P. Laurent, Eric Delabesse, Carole Barin Bonnigal, Damien Roos-Weil, Olivier A. Bernard, Beat Bornhauser, M'Boyba Diop, Paola Ballerini, Sébastien Malinge, Aurelie Siret, Yi Chien Tsai, Cathy Ignacimouttou, Silvia Jenni, Zakia Aid, Naïs Prade, Jean-Pierre Bourquin, Thomas Mercher, Laurence C. Cheung, John D. Crispino, Rishi S. Kotecha, Birgit Geoerger, Gaëlle Pierron, Nathalie Droin, Muriel Gaudry, University of Zurich, 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, Institut Gustave Roussy (IGR), The University of Western Australia (UWA), 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), University Children’s Hospital Zurich, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Curtin University [Perth], Planning and Transport Research Centre (PATREC), Northwestern University [Chicago, Ill. USA], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Perth Children's Hospital [Nedlands, WA, Australia], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris-Sorbonne (UP4), and univOAK, Archive ouverte

Subjects
0301 basic medicine, MAPK/ERK pathway, Cancer Research, Vincristine, Pyridones, Mice, Transgenic, 610 Medicine & health, [SDV.GEN] Life Sciences [q-bio]/Genetics, Pyrimidinones, Article, Immunophenotyping, 03 medical and health sciences, Mice, 0302 clinical medicine, Leukemia, B-Cell, Medicine, Animals, Humans, 1306 Cancer Research, Protein Kinase Inhibitors, Trametinib, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, MEK inhibitor, Gene Expression Profiling, Computational Biology, Oncogenes, medicine.disease, Leukemia, Disease Models, Animal, 030104 developmental biology, Oncology, 10036 Medical Clinic, 030220 oncology & carcinogenesis, B-cell leukemia, Cancer research, ras Proteins, 2730 Oncology, Disease Susceptibility, Down Syndrome, Mitogen-Activated Protein Kinases, business, Trisomy, Chromosome 21, medicine.drug, Signal Transduction
Abstract

Purpose: Children with Down syndrome (constitutive trisomy 21) that develop acute lymphoblastic leukemia (DS-ALL) have a 3-fold increased likelihood of treatment-related mortality coupled with a higher cumulative incidence of relapse, compared with other children with B-cell acute lymphoblastic leukemia (B-ALL). This highlights the lack of suitable treatment for Down syndrome children with B-ALL. Experimental Design: To facilitate the translation of new therapeutic agents into clinical trials, we built the first preclinical cohort of patient-derived xenograft (PDX) models of DS-ALL, comprehensively characterized at the genetic and transcriptomic levels, and have proven its suitability for preclinical studies by assessing the efficacy of drug combination between the MEK inhibitor trametinib and conventional chemotherapy agents. Results: Whole-exome and RNA-sequencing experiments revealed a high incidence of somatic alterations leading to RAS/MAPK pathway activation in our cohort of DS-ALL, as well as in other pediatric B-ALL presenting somatic gain of the chromosome 21 (B-ALL+21). In murine and human B-cell precursors, activated KRASG12D functionally cooperates with trisomy 21 to deregulate transcriptional networks that promote increased proliferation and self renewal, as well as B-cell differentiation blockade. Moreover, we revealed that inhibition of RAS/MAPK pathway activation using the MEK1/2 inhibitor trametinib decreased leukemia burden in several PDX models of B-ALL+21, and enhanced survival of DS-ALL PDX in combination with conventional chemotherapy agents such as vincristine. Conclusions: Altogether, using novel and suitable PDX models, this study indicates that RAS/MAPK pathway inhibition represents a promising strategy to improve the outcome of Down syndrome children with B-cell precursor leukemia.

Published
2020

22. B-cell tumor development in Tet2-deficient mice

Author

Cécile K. Lopez, Philippe Dessen, Michaela Fontenay, Hussein Ghamlouch, Patrycja Pawlikowska, Olivier Bernard, Cyril Quivoron, Véronique Saada, Enguerran Mouly, Laurianne Scourzic, Said Aoufouchi, Ivo P. Touw, M'Boyba Diop, Damien Roos-Weil, Thomas Mercher, Véronique Della-Valle, Différenciation des cellules B, hémopathies, lymphoïdes et déficit de l'immunité humorale, Université Paris Diderot - Paris 7 ( UPD7 ), Génétique des hémopathies humaines ( EMI 210 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Gustave Roussy ( IGR ), 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 ), Immunology-Hematology, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Génomes et cancer ( GC (FRE2939) ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), Développement du Systeme Immunitaire, Liquides Ioniques et Interfaces Chargées ( LI2C ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -ESPCI ParisTech-Centre National de la Recherche Scientifique ( CNRS ), and Hematology

Subjects
0301 basic medicine, APOBEC, Lymphoma, B-Cell, Myeloid, Genotype, Cell Survival, Chronic lymphocytic leukemia, Receptors, Antigen, B-Cell, Biology, Dioxygenases, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 03 medical and health sciences, Proto-Oncogene Proteins, Leukemia, B-Cell, medicine, Animals, Genetic Predisposition to Disease, Alleles, Genetic Association Studies, B cell, Mice, Knockout, B-Lymphocytes, Lymphoid Neoplasia, breakpoint cluster region, Hematology, Flow Cytometry, medicine.disease, DNA-Binding Proteins, Leukemia, 030104 developmental biology, DNA demethylation, medicine.anatomical_structure, Mutation, Cancer research, CD5, Biomarkers
Abstract

International audience; The TET2 gene encodes an α-ketoglutarate-dependent dioxygenase able to oxidize 5-methylcytosine into 5-hydroxymethylcytosine, which is a step toward active DNA demethylation. TET2 is frequently mutated in myeloid malignancies but also in B- and T-cell malignancies. TET2 somatic mutations are also identified in healthy elderly individuals with clonal hematopoiesis. Tet2-deficient mouse models showed widespread hematological differentiation abnormalities, including myeloid, T-cell, and B-cell malignancies. We show here that, similar to what is observed with constitutive Tet2-deficient mice, B-cell-specific Tet2 knockout leads to abnormalities in the B1-cell subset and a development of B-cell malignancies after long latency. Aging Tet2-deficient mice accumulate clonal CD19+ B220low immunoglobulin M+ B-cell populations with transplantable ability showing similarities to human chronic lymphocytic leukemia, including CD5 expression and sensitivity to ibrutinib-mediated B-cell receptor (BCR) signaling inhibition. Exome sequencing of Tet2-/- malignant B cells reveals C-to-T and G-to-A mutations that lie within single-stranded DNA-specific activation-induced deaminase (AID)/APOBEC (apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like) cytidine deaminases targeted motif, as confirmed by the lack of a B-cell tumor in compound Tet2-Aicda-deficient mice. Finally, we show that Tet2 deficiency accelerates and exacerbates T-cell leukemia/lymphoma 1A-induced leukemogenesis. Together, our data establish that Tet2 deficiency predisposes to mature B-cell malignancies, which development might be attributed in part to AID-mediated accumulating mutations and BCR-mediated signaling.

Published
2018

23. ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia

Author

Arnaud Petit, Françoise Pflumio, Cécile Thirant, Cécile K. Lopez, Sébastien Malinge, Hana Raslova, Aurelie Siret, Olivier A. Bernard, Clarisse Thiollier, Cathy Ignacimouttou, Mehdi Khaled, M'Boyba Diop, Jürg Schwaller, William Vainchenker, John D. Crispino, Paola Ballerini, Guy Leverger, Ce ' Line Lefebvre, Philippe Rameau, Benjamin T. Kile, Catherine Carmichael, Lou Le Mouel, Eric Soler, Phillipe Dessen, Thomas Mercher, Zakia Aid, Julie Riviere, Nathalie Droin, Christian Wichmann, Camille Lobry, 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 ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plateforme imagerie et cytométrie ( PFIC ), 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 ), Ondes et Imagerie ( O&I ), Laboratoire de Mécanique et d'Acoustique [Marseille] ( LMA ), Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ) -Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ), Hôpital Trousseau, CHRU Tours, CHU Trousseau [APHP], Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ), Centre de génétique et de physiologie moléculaire et cellulaire ( CGPhiMC ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Northwestern University Chicago, Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ), Plateforme de génomique, Laboratoire des Adaptations Physiologiques aux Activités Physiques ( LAPHAP ), Université de Poitiers, Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ) -Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), and Université de Lyon-Université de Lyon

Subjects
Transcriptional Activation, 0301 basic medicine, Cancer Research, Oncogene Proteins, Fusion, ChIP, Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 03 medical and health sciences, Acute megakaryoblastic leukemia, Transcriptional Regulator ERG, GLIS2, Downregulation and upregulation, Leukemia, Megakaryoblastic, Acute, Transcription (biology), medicine, Animals, Humans, GATA1 Transcription Factor, Child, Enhancer, Gene, Transcription factor, transcription factor, CBFA2T3, AMKL, leukemia, Cell Differentiation, GLIS, medicine.disease, Leukemia, pediatric, Enhancer Elements, Genetic, 030104 developmental biology, Oncology, ERG, CRISPR, Cancer research, enhancer
Abstract

International audience; Chimeric transcription factors are a hallmark of human leukemia, but the molecular mechanisms by which they block differentiation and promote aberrant self-renewal remain unclear. Here, we demonstrate that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. ETO2-GLIS2 directly binds DNA to control transcription of associated genes by upregulation of expression and interaction with the ETS-related ERG protein at enhancer elements. Importantly, specific interference with ETO2-GLIS2 oligomerization reverses the transcriptional activation at enhancers and promotes megakaryocytic differentiation, providing a relevant interface to target in this poor-prognosis pediatric leukemia.

Published
2017

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

Author

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

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

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

Published
2019

25. Ontogenic changes in hematopoietic hierarchy determine pediatric specificity and disease phenotype in fusion oncogene-driven myeloid leukemia

Author

Cécile K. Lopez, Marie Laure Arcangeli, Eric Delabesse, Sébastien Malinge, Alexandre Fagnan, Isabelle Godin, Franco Locatelli, Françoise Pflumio, Fabien Boudia, Cécile Thirant, Muriel Gaudry, Vaia Stavropoulou, Arnaud Petit, Claus Nerlov, Nathalie Droin, Riccardo Masetti, Paola Ballerini, Zakia Aid, Berthold Göttgens, Olivier Bernard, Sarah Kinston, Erika Brunet, Hélène Lapillonne, Loelia Babin, Juerg Schwaller, Antoine H.F.M. Peters, Elie Robert, Yann Lécluse, Bastien Job, Chrystele Bilhou-Nabera, Jean-Luc Villeval, Camille Lobry, William Vainchenker, Thomas Mercher, Esteve Noguera, M'Boyba Diop, Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Stabilité génétique, Cellules Souches et Radiations (SCSR (U_967)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), 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), 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), Bases fondamentales et stratégies nouvelles en cancérologie (BFSNC - IFR54), 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), Régulation et dynamique des génomes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Santa Lucia Foundation, IRCSS, Rome, University of Oxford [Oxford], Images et Modèles, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Cambridge [UK] (CAM), Service Procédés et Innovations Industriels (SPII), eRcane, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique des tumeurs (U985), Institut Gustave Roussy (IGR)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), 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), Centre de Recherche et d'Etude en Droit et Science Politique (CREDESPO), Université de Bourgogne (UB), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lopez C.K., Noguera E., Stavropoulou V., Robert E., Aid Z., Ballerini P., Bilhou-Nabera C., Lapillonne H., Boudia F., Thirant C., Fagnan A., Arcangeli M.-L., Kinston S.J., Diop M., Job B., Lecluse Y., Brunet E., Babin L., Villeval J.L., Delabesse E., Peters A.H.F.M., Vainchenker W., Gaudry M., Masetti R., Locatelli F., Malinge S., Nerlov C., Droin N., Lobry C., Godin I., Bernard O.A., Gottgens B., Petit A., Pflumio F., Schwaller J., Mercher T., Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire d'Hématologie [AP-HP Hôpital Armand Trousseau], Cellules Souches et Radiations (SCSR (U967 / UMR-E_008)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-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)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Brunet, Erika [0000-0002-1726-4673], Malinge, Sébastien [0000-0002-9533-7778], Droin, Nathalie [0000-0002-6099-5324], Godin, Isabelle [0000-0001-8577-8388], Göttgens, Berthold [0000-0001-6302-5705], Schwaller, Juerg [0000-0001-8616-0096], Mercher, Thomas [0000-0003-1552-087X], Apollo - University of Cambridge Repository, Centre de Psychiatrie et Neurosciences (U894), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Oxford, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Myeloid, Oncogene Proteins, Fusion, Oncogene Proteins, Fusion gene, Mice, 0302 clinical medicine, AML, CEBPA, GENOMIC ALTERATIONS, Tumor Cells, Cultured, TRANSCRIPTION FACTOR, RNA-SEQ, Child, ComputingMilieux_MISCELLANEOUS, GENE-EXPRESSION, Age Factors, Myeloid leukemia, GATA1, 3. Good health, Leukemia, Myeloid, Acute, Leukemia, Haematopoiesis, medicine.anatomical_structure, DIFFERENTIATION, Oncology, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Child, Preschool, 030220 oncology & carcinogenesis, Female, Adolescent, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, children, ACUTE MEGAKARYOBLASTIC LEUKEMIA, transcription factors, medicine, Animals, Humans, FETAL, pediatric acute myeloid leukemia, LINEAGE COMMITMENT, Infant, medicine.disease, STEM-CELL, SELF-RENEWAL, 030104 developmental biology, Cancer research, Neoplasm Transplantation
Abstract

Fusion oncogenes are prevalent in several pediatric cancers, yet little is known about the specific associations between age and phenotype. We observed that fusion oncogenes, such as ETO2–GLIS2, are associated with acute megakaryoblastic or other myeloid leukemia subtypes in an age-dependent manner. Analysis of a novel inducible transgenic mouse model showed that ETO2–GLIS2 expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in adult bone marrow hematopoietic stem cells resulted in a shift toward myeloid transformation with a strikingly delayed in vivo leukemogenic potential. Chromatin accessibility and single-cell transcriptome analyses indicate ontogeny-dependent intrinsic and ETO2–GLIS2-induced differences in the activities of key transcription factors, including ERG, SPI1, GATA1, and CEBPA. Importantly, switching off the fusion oncogene restored terminal differentiation of the leukemic blasts. Together, these data show that aggressiveness and phenotypes in pediatric acute myeloid leukemia result from an ontogeny-related differential susceptibility to transformation by fusion oncogenes. Significance: This work demonstrates that the clinical phenotype of pediatric acute myeloid leukemia is determined by ontogeny-dependent susceptibility for transformation by oncogenic fusion genes. The phenotype is maintained by potentially reversible alteration of key transcription factors, indicating that targeting of the fusions may overcome the differentiation blockage and revert the leukemic state. See related commentary by Cruz Hernandez and Vyas, p. 1653. This article is highlighted in the In This Issue feature, p. 1631

Published
2019

26. Engraftment of chronic myelomonocytic leukemia cells in immunocompromised mice supports disease dependency on cytokines

Author

Chloe Jego, Valérie Lapierre, Eric Solary, M'Boyba Diop, Fawzia Louache, Patrick Gonin, Liang He, Margot Morabito, Christophe Willekens, Yanyan Zhang, Dorothée Selimoglu-Buet, and Nathalie Droin

Subjects
0301 basic medicine, Severe combined immunodeficiency, Myeloid Neoplasia, CD34, Chronic myelomonocytic leukemia, Stem cell factor, Hematology, Biology, Gene mutation, medicine.disease, Colony-stimulating factor, 03 medical and health sciences, 030104 developmental biology, Granulocyte macrophage colony-stimulating factor, medicine.anatomical_structure, hemic and lymphatic diseases, Immunology, medicine, Bone marrow, medicine.drug
Abstract

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder that typically associates with mutations in epigenetic, splicing, and signaling genes. Genetically modified mouse models only partially recapitulate the disease phenotype, whereas xenotransplantation of CMML cells in immunocompromised mice has been rarely successful so far. Here, CMML CD34+ cells sorted from patient bone marrow (BM) or peripheral blood (PB) were injected intravenously into NSG (NOD/LtSz-scid IL2rγnull) mice and NSG mice engineered to express human granulo-monocyte colony-stimulating factor, stem cell factor, and interleukin-3 (NSGS mice). Fifteen out of 16 patient samples (94%) successfully engrafted into NSG or NSGS or both mouse strains. The expansion of human cells, predominant in the BM, was also observed in the spleen and the PB and was greatly enhanced in mice producing the 3 human cytokines. Gene mutations identified in engrafted cells were mostly similar to those identified in patient cells before injection. Successful secondary engraftment was obtained in NSGS mice in 3 out of 10 attempts. Thus, primary CMML leukemic cells expand much better in NSGS compared with NSG mice with limited efficacy of secondary transplant.

Published
2017

27. PF151 RAS/MAPK ACTIVATION COOPERATES WITH GAIN OF CHROMOSOME 21 IN B CELL LEUKEMIA AND IS AN ATTRACTIVE TARGET TO IMPROVE THE OUTCOME OF DS CHILDREN WITH B-ALL

Author

G. Meurice, Yi Chien Tsai, Cathy Ignacimouttou, C. Barin Bonnigal, Aurelie Siret, Beat Bornhauser, Sébastien Malinge, H. Aid, Naïs Prade, Damien Roos-Weil, Olivier A. Bernard, Elizabeth Macintyre, Eric Delabesse, M'Boyba Diop, Laurence C. Cheung, D. Plassard, Jean-Pierre Bourquin, Stéphanie Lagarde, Thomas Mercher, Rishi S. Kotecha, Paola Ballerini, and Anouchka P. Laurent

Subjects
Ras mapk, B-cell leukemia, Cancer research, medicine, Hematology, Biology, medicine.disease, Chromosome 21
Published
2019

28. Acquired TET2 mutation in one patient with familial platelet disorder with predisposition to AML led to the development of pre-leukaemic clone resulting in T2-ALL and AML-M0

Author

Vladimir T, Manchev, Hind, Bouzid, Iléana, Antony-Debré, Betty, Leite, Guillaume, Meurice, Nathalie, Droin, Thomas, Prebet, Régis T, Costello, William, Vainchenker, Isabelle, Plo, M'boyba, Diop, Elizabeth, Macintyre, Vahid, Asnafi, Rémi, Favier, Véronique, Baccini, and Hana, Raslova

Subjects
Adult, Blood Platelets, Male, TET2, RUNX1, Short Communication, AML‐M0, High-Throughput Nucleotide Sequencing, Antigens, CD34, Dioxygenases, DNA-Binding Proteins, Leukemia, Myeloid, Acute, hemic and lymphatic diseases, Proto-Oncogene Proteins, Core Binding Factor Alpha 2 Subunit, Humans, Blood Platelet Disorders, predisposition to leukaemia, T2‐ALL, FPD/AML
Abstract

Familial platelet disorder with predisposition to acute myeloid leukaemia (FPD/AML) is characterized by germline RUNX1 mutations, thrombocytopaenia, platelet dysfunction and a risk of developing acute myeloid and in rare cases lymphoid T leukaemia. Here, we focus on a case of a man with a familial history of RUNX1 R174Q mutation who developed at the age of 42 years a T2‐ALL and, 2 years after remission, an AML‐M0. Both AML‐M0 and T2‐ALL blast populations demonstrated a loss of 1p36.32‐23 and 17q11.2 regions as well as other small deletions, clonal rearrangements of both TCRγ and TCRδ and a presence of 18 variants at a frequency of more than 40%. Additional variants were identified only in T2‐ALL or in AML‐M0 evoking the existence of a common original clone, which gave rise to subclonal populations. Next generation sequencing (NGS) performed on peripheral blood‐derived CD34+ cells 5 years prior to T2‐ALL development revealed only the missense TET2 P1962T mutation at a frequency of 1%, which increases to more than 40% in fully transformed leukaemic T2‐ALL and AML‐M0 clones. This result suggests that TET2 P1962T mutation in association with germline RUNX1 R174Q mutation leads to amplification of a haematopoietic clone susceptible to acquire other transforming alterations.

Published
2016

29. DNMT3AR882H mutant and Tet2 inactivation cooperate in the deregulation of DNA methylation control to induce lymphoid malignancies in mice

Author

Cécile K. Lopez, Kristian Helin, Elena Mylonas, Michaela Fontenay, Enguerran Mouly, Françoise Pflumio, P. Gaulard, Marianne Terndrup Pedersen, M'Boyba Diop, Michael Weber, Laurianne Scourzic, Lucile Couronné, Nathalie Droin, O. Bernard, Julien Calvo, Patrice Dubreuil, Ambre Bender, Philippe Dessen, N Martin, V Della Valle, Sylvain Guibert, Thomas Mercher, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), 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 ), Institut Gustave Roussy ( IGR ), Génétique des tumeurs ( U985 ), Institut Gustave Roussy ( IGR ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Norwegian Defence Intelligence School [Oslo] ( NDUC ), Centre de recherche en économie et management ( CREM ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ), Centro de Aplicaciones de Tecnologías de Avanzada ( CENATAV ), CENATAV, Laboratoire Ligérien de Linguistique ( LLL ), Bibliothèque nationale de France ( BnF ) -Université d'Orléans ( UO ) -Université de Tours-Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), The Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge [UK] ( CAM ), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Images et Modèles, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé ( CREATIS ), Université Jean Monnet [Saint-Étienne] ( UJM ) -Hospices Civils de Lyon ( HCL ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Hospices Civils de Lyon ( HCL ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), and Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
0301 basic medicine, Cancer Research, Myeloid, Cellular differentiation, Notch signaling pathway, Biology, Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire, medicine.disease_cause, Article, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, DNA Methyltransferase 3A, Dioxygenases, 03 medical and health sciences, Mice, Proto-Oncogene Proteins, medicine, Animals, Genes, Tumor Suppressor, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, DNA (Cytosine-5-)-Methyltransferases, Mutation, Receptors, Notch, Myeloid leukemia, Cell Differentiation, Hematology, DNA Methylation, Lymphoproliferative Disorders, Transplantation, Gene expression profiling, DNA-Binding Proteins, 030104 developmental biology, medicine.anatomical_structure, Oncology, embryonic structures, DNA methylation, Immunology, Cancer research
Abstract

International audience; TEN-ELEVEN-TRANSLOCATION-2 (TET2) and DNA-METHYLTRANSFERASE-3A (DNMT3A), both encoding proteins involved in regulating DNA methylation, are mutated in hematological malignancies affecting both myeloid and lymphoid lineages. We previously reported an association of TET2 and DNMT3A mutations in progenitors of patients with angioimmunoblastic T-cell lymphomas (AITL). Here, we report on the cooperative effect of Tet2 inactivation and DNMT3A mutation affecting arginine 882 (DNMT3A(R882H)) using a murine bone marrow transplantation assay. Five out of eighteen primary recipients developed hematological malignancies with one mouse developing an AITL-like disease, two mice presenting acute myeloid leukemia (AML)-like and two others T-cell acute lymphoblastic leukemia (T-ALL)-like diseases within 6 months following transplantation. Serial transplantations of DNMT3A(R882H) Tet2(-/-) progenitors led to a differentiation bias toward the T-cell compartment, eventually leading to AITL-like disease in 9/12 serially transplanted recipients. Expression profiling suggested that DNMT3A(R882H) Tet2(-/-) T-ALLs resemble those of NOTCH1 mutant. Methylation analysis of DNMT3A(R882H) Tet2(-/-) T-ALLs showed a global increase in DNA methylation affecting tumor suppressor genes and local hypomethylation affecting genes involved in the Notch pathway. Our data confirm the transformation potential of DNMT3A(R882H) Tet2(-/-) progenitors and represent the first cooperative model in mice involving Tet2 inactivation driving lymphoid malignancies.

Published
2016

30. Architectural and functional heterogeneity of hematopoietic stem/progenitor cells in non-del(5q) myelodysplastic syndromes

Author

M'Boyba Diop, Carine Lefevre, Sophie Raynaud, Nicolas Chapuis, Marie-Laure Arcangeli, Meyling Cheok, Lise Willems, Laurence Legros, Evelyne Lauret, Caroline Delette, Virginie Chesnais, Didier Bouscary, Sabrina Bondu, Alice Rousseau, Hélène Guermouche, Olivier A. Bernard, Michaela Fontenay, Françoise Pflumio, and Olivier Kosmider

Subjects
0301 basic medicine, Myeloid, Clone (cell biology), Gene Expression, Antigens, CD34, Cell Cycle Proteins, Gene mutation, Biochemistry, Mice, 0302 clinical medicine, Mice, Inbred NOD, hemic and lymphatic diseases, Myeloid Cells, Lymphocytes, Genetics, Membrane Glycoproteins, Hematopoietic stem cell, Myeloid leukemia, Antigens, Nuclear, Cell Differentiation, Hematology, Haematopoiesis, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Phenotype, 030220 oncology & carcinogenesis, Gene Knockdown Techniques, Disease Progression, Chromosomes, Human, Pair 5, Female, Lineage (genetic), Immunology, Transplantation, Heterologous, Biology, Immunophenotyping, 03 medical and health sciences, Proto-Oncogene Proteins, medicine, Animals, Humans, Cell Lineage, Progenitor cell, Cell Biology, Hematopoietic Stem Cells, ADP-ribosyl Cyclase 1, Clone Cells, Repressor Proteins, 030104 developmental biology, Myelodysplastic Syndromes, Mutation, Cancer research
Abstract

Myelodysplastic syndromes (MDSs) are hematopoietic stem cell disorders in which recurrent mutations define clonal hematopoiesis. The origin of the phenotypic diversity of non-del(5q) MDS remains unclear. Here, we investigated the clonal architecture of the CD34+CD38- hematopoietic stem/progenitor cell (HSPC) compartment and interrogated dominant clones for MDS-initiating cells. We found that clones mainly accumulate mutations in a linear succession with retention of a dominant subclone. The clone detected in the long-term culture-initiating cell compartment that reconstitutes short-term human hematopoiesis in xenotransplantation models is usually the dominant clone, which gives rise to the myeloid and to a lesser extent to the lymphoid lineage. The pattern of mutations may differ between common myeloid progenitors (CMPs), granulomonocytic progenitors (GMPs), and megakaryocytic-erythroid progenitors (MEPs). Rare STAG2 mutations can amplify at the level of GMPs, from which it may drive the transformation to acute myeloid leukemia. We report that major truncating BCOR gene mutation affecting HSPC and CMP was beneath the threshold of detection in GMP or MEP. Consistently, BCOR knock-down (KD) in normal CD34+ progenitors modifies their granulocytic and erythroid differentiation. Clonal architecture of the HSPC compartment and mutations selected during differentiation contribute to the phenotypic heterogeneity of MDS. Defining the hierarchy of driver mutations provides insights into the process of transformation and may guide the search for novel therapeutic strategies.

Published
2016

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

Author

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

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

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

Published
2018

32. Presence of atypical thrombopoietin receptor (MPL) mutations in triple negative essential thrombocythemia patients

Author

William Vainchenker, Jean-Philippe Defour, Fabrizia Favale, Valérie Ugo, Stefan N. Constantinescu, Jean Christophe Ianotto, Olivier Bluteau, Nathalie Droin, Christine Bellanné-Chantelot, Kahia Messaoudi, Jean Pierre Le Couédic, Hana Raslova, Isabelle Plo, Nicole Casadevall, Florence Pasquier, M'Boyba Diop, Ilyas Chachoua, Xenia Cabagnols, Christophe Marzac, Rémi Favier, Najet Debili, Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), De Duve Institute, Université Catholique de Louvain = Catholic University of Louvain (UCL), Ludwig Institute for Cancer Research (LICR - BRUSSELS), Ludwig Institute for Cancer Research, Département d'Hématologie Clinique (BREST - Hémato Clinique), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), 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)-Université de Brest (UBO), Territoires, économie, enjeux sociétaux (LARHRA TEES), LAboratoire de Recherche Historique Rhône-Alpes - UMR5190 (LARHRA), Université Pierre Mendès France - Grenoble 2 (UPMF)-École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire d’Océanologie et de Géosciences (LOG) - UMR 8187 (LOG), Institut national des sciences de l'Univers (INSU - CNRS)-Université du Littoral Côte d'Opale (ULCO)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Nord]), Laboratoire d'Hématologie Biologique, Service de Génétique Cytogénétique et Embryologie [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), Laboratoire d'Excellence du Globule Rouge, Villejuif, France, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Centre National de la Recherche Scientifique (CNRS)-Université du Littoral Côte d'Opale (ULCO)-Université de Lille-Institut national des sciences de l'Univers (INSU - CNRS), UCL - (SLuc) Service de biologie hématologique, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/SIGN - Cell signalling, Université Pierre Mendès France - Grenoble 2 (UPMF)-École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, medicine.disease_cause, Biochemistry, Cohort Studies, 0302 clinical medicine, hemic and lymphatic diseases, Medicine, Exome, Mutation, Comparative Genomic Hybridization, Janus kinase 2, thrombopoietin receptor, biology, essential thrombocythemia, food and beverages, High-Throughput Nucleotide Sequencing, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Protein Transport, 030220 oncology & carcinogenesis, NGS, Cytokines, Receptors, Thrombopoietin, Thrombocythemia, Essential, Genotype, Immunology, Cell Line, 03 medical and health sciences, Humans, Codon, Allele frequency, Thrombopoietin, Myeloproliferative neoplasm, Cell Proliferation, Thrombopoietin receptor, business.industry, Essential thrombocythemia, Whole exome sequencing, Cell Biology, Janus Kinase 2, medicine.disease, mutations, Molecular biology, 030104 developmental biology, Amino Acid Substitution, biology.protein, business, Calreticulin, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Granulocytes
Abstract

International audience; Mutations in signaling molecules of the cytokine receptor axis play a central role in myeloproliferative neoplasm (MPN) pathogenesis. Polycythemia Vera is mainly related to JAK2 mutations, whereas a wider mutational spectrum is detected in Essential Thrombocythemia (ET) with mutations in JAK2, the thrombopoietin receptor (MPL) and the calreticulin (CALR) genes. Here, we studied the mutational profile of 17 ET patients negative for JAK2V617F, MPLW515K/L and CALR mutations, using Whole Exome Sequencing and Next Generation Sequencing (NGS) targeted on JAK2 and MPL. We found several signaling mutations including JAK2V617F at very low allele frequency, one homozygous SH2B3 mutation, one MPLS505N, one MPLW515R and two MPLS204P mutations. In the remaining patients, four presented a clonal and seven a polyclonal hematopoiesis, suggesting that certain triple negative ETs are not MPNs. NGS on 26 additional triple negative ETs detected only one MPLY591N mutation. Functional studies on MPLS204P and MPLY591N revealed that they are weak gain-of-function mutants increasing MPL signaling and conferring either TPO hypersensitivity or independence to expressing cells, but with a low efficiency. Further studies should be performed to precisely determine the frequency of MPLS204 and MPLY591 mutants in a bigger cohort of MPN.

Published
2015

33. Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies

Author

Hana Raslova, Eric Solary, Sabine Charrier, Jane Merlevede, Gaëlle Lenglet, Antonio Di Stefano, M'Boyba Diop, Véronique Della Valle, Gwendoline Leroy, Boris Keren, Cécile Saint-Martin, Christine Bellanné-Chantelot, Sarah Grosjean, Lise Secardin, Philippe Dessen, Caroline Marty, Nicole Casadevall, Emna Mahfoudhi, Najet Debili, Florence Pasquier, Isabelle Plo, Françoise Isnard, Joseph Saliba, Pascal Fuseau, Albert Najman, Jean-Côme Meniane, Olivier Bernard, Christine Delaunay-Darivon, Alberta Palazzo, William Vainchenker, Nathalie Droin, HAL, Univ Évry, 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hématopoïèse normale et pathologique, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, CHU Saint-Antoine [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC), École Pratique des Hautes Études (EPHE), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11)

Subjects
Adult, Male, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Myeloid, Adolescent, Induced Pluripotent Stem Cells, Vesicular Transport Proteins, Autophagy-Related Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Germline, Young Adult, [SDV.CAN] Life Sciences [q-bio]/Cancer, Gene Duplication, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Gene duplication, Genetics, medicine, Humans, Genetic Predisposition to Disease, Induced pluripotent stem cell, Child, Thrombopoietin, Aged, Chromosomes, Human, Pair 14, Myelodysplastic syndromes, Infant, food and beverages, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.disease, Phenotype, Pedigree, Repressor Proteins, Leukemia, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Germ Cells, Myelodysplastic Syndromes, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female
Abstract

International audience; No major predisposition gene for familial myeloproliferative neoplasms (MPN) has been identified. Here we demonstrate that the autosomal dominant transmission of a 700-kb duplication in four genetically related families predisposes to myeloid malignancies, including MPN, frequently progressing to leukemia. Using induced pluripotent stem cells and primary cells, we demonstrate that overexpression of ATG2B and GSKIP enhances hematopoietic progenitor differentiation, including of megakaryocytes, by increasing progenitor sensitivity to thrombopoietin (TPO). ATG2B and GSKIP cooperate with acquired JAK2, MPL and CALR mutations during MPN development. Thus, the germline duplication may change the fitness of cells harboring signaling pathway mutations and increases the probability of disease development.

Published
2015

34. Acquired initiating mutations in early hematopoietic cells of CLL patients

Author

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

Subjects
Chronic lymphocytic leukemia, Receptors, Antigen, B-Cell, Biology, medicine.disease_cause, Somatic evolution in cancer, Article, immune system diseases, hemic and lymphatic diseases, medicine, Cluster Analysis, Humans, neoplasms, Mutation, Gene Expression Profiling, Multipotent Stem Cells, breakpoint cluster region, Cancer, Ribonucleoprotein, U2 Small Nuclear, medicine.disease, Hematopoietic Stem Cells, Phosphoproteins, Phenotype, NFKBIE, Leukemia, Lymphocytic, Chronic, B-Cell, Oncology, Multipotent Stem Cell, Immunology, RNA Splicing Factors, Immunoglobulin Heavy Chains, Signal Transduction
Abstract

Appropriate cancer care requires a thorough understanding of the natural history of the disease, including the cell of origin, the pattern of clonal evolution, and the functional consequences of the mutations. Using deep sequencing of flow-sorted cell populations from patients with chronic lymphocytic leukemia (CLL), we established the presence of acquired mutations in multipotent hematopoietic progenitors. Mutations affected known lymphoid oncogenes, including BRAF, NOTCH1, and SF3B1. NFKBIE and EGR2 mutations were observed at unexpectedly high frequencies, 10.7% and 8.3% of 168 advanced-stage patients, respectively. EGR2 mutations were associated with a shorter time to treatment and poor overall survival. Analyses of BRAF and EGR2 mutations suggest that they result in deregulation of B-cell receptor (BCR) intracellular signaling. Our data propose disruption of hematopoietic and early B-cell differentiation through the deregulation of pre-BCR signaling as a phenotypic outcome of CLL mutations and show that CLL develops from a pre-leukemic phase. Significance: The origin and pathogenic mechanisms of CLL are not fully understood. The current work indicates that CLL develops from pre-leukemic multipotent hematopoietic progenitors carrying somatic mutations. It advocates for abnormalities in early B-cell differentiation as a phenotypic convergence of the diverse acquired mutations observed in CLL. Cancer Discov; 4(9); 1088–1101. ©2014 AACR. See related commentary by Jiang and Elemento, p. 995 This article is highlighted in the In This Issue feature, p. 973

Published
2014

35. ETO2-GLIS2 Controls Differentiation Arrest and Self-Renewal through Aberrant Enhancers Regulation in Pediatric Leukemia

Author

Benjamin T. Kile, Lou Le Mouel, Aurelie Siret, William Vainchenker, Philippe Rameau, Catherine Carmichael, Clarisse Thiollier, Sébastien Malinge, Hana Raslova, Mehdi Khaled, M'Boyba Diop, Olivier A. Bernard, John D. Crispino, Eric Soler, Cécile K. Lopez, Thomas Mercher, Philippe Dessen, Cathy Ignacimouttou, Camille Lobry, Zakia Aid, Francoise Pfumio, Cécile Thirant, Juerg Schwaller, Paola Ballerini, Arnaud Petit, Guy Leverger, Celine Lefebvre, Nathalie Droin, Julie Riviere, and Christian Wichmann

Subjects
Genetics, Gene knockdown, Immunology, Myeloid leukemia, Cell Biology, Hematology, Biology, medicine.disease, Biochemistry, Cell biology, Gene expression profiling, Fusion gene, Acute megakaryoblastic leukemia, medicine, Transcriptional regulation, Enhancer, Transcription factor
Abstract

Deregulated gene expression due to genetic alterations, such as gene fusions affecting transcription and/or epigenetic factors is the hallmark of acute myeloid leukemia and the basis for the differentiation block of hematopoietic progenitors. Acute megakaryoblastic leukemia (AMKL) is a subtype of poor prognosis acute myeloid leukemia (AML) affecting primarily young children. Recently, the ETO2-GLIS2 fusion has been identified in 20-30% of de novo AMKL and associated with the worst prognosis in this subtype of AML. To characterize the transformation induced by ETO2-GLIS2, we first defined the consequences of ETO2-GLIS2 expression on hematopoietic progenitors and the contribution of ETO2 and GLIS2 on differentiation and self-renewal. Using methylcellulose replating assays and phenotype characterization, we show that the GLIS2 moiety drives the megakaryocytic phenotype whereas both the ETO2 and GLIS2 moieties are required for maintaining self-renewal. Global expression profiling and comparison to patients' signature consistently identify ETO2-GLIS2-mediated deregulation of major transcriptional regulators of hematopoiesis and leukemogenesis, including overexpression of the ERG oncogene. ChIP-seq analysis reveals that ETO2-GLIS2 is recruited at normal ETO2 complexes sites and also at GLIS2-specific targets through binding via GLIS2 DNA-binding domain. We demonstrate that ETO2-GLIS2 fusion localize at half of H3K27Ac-dense enhancers, so called super-enhancers, to control transcription of associated genes. We show that interaction of ETO2-GLIS2 with ETO2 complexes is an essential node for the transcriptional control by the fusion at enhancer elements. Indeed, ETO2-GLIS2 dimerizes and interacts with endogenous ETO2 via its NHR2 domains. An NHR2 peptide-interference strategy inhibits oligomerization, reverses the transcriptional activation at enhancers, promotes megakaryocytic differentiation and abrogates human AMKL cells maintenance in vivo. Finally, upregulation of ERG by ETO2-GLIS2 further strengthen enhancers formation as ERG is co-recruited generating a feed forward loop at these elements and its knockdown or genetic inactivation downregulates expression of ETO2-GLIS2 targets required for leukemic cells survival. We propose that the megakaryocytic differentiation arrest and self-renewal controlled by ETO2-GLIS2 results from an imbalance in the expression of master transcription factors imposed by aberrant chromatin structures at enhancers that may be disrupted by targeting the NHR2 interface. Disclosures No relevant conflicts of interest to declare.

Published
2016

36. Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models

Author

Arnaud Petit, Clarisse Thiollier, Paola Rivera-Munoz, Françoise Pflumio, Daniel Gautheret, Justine Guegan, William Vainchenker, Paola Ballerini, Judith Landman-Parker, Philippe Dessen, Yannis Duffourd, Cécile K. Lopez, Isabelle Radford, M'Boyba Diop, John D. Crispino, Olivier Bluteau, Yann Lécluse, Thomas Mercher, Beat Bornhauser, Stéphane de Botton, Jean-Pierre Bourquin, Cathy Ignacimouttou, Olivier Bernard, Dirk Reinhardt, Sandrine Poglio, Vinciane Mabialah, Nicole Dastugue, Anne Laure Bauchet, Bastien Gerby, Qiang Wen, Institut Gustave Roussy (IGR), Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service MIRCEN (MIRCEN), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Hannover Medical School [Hannover] (MHH), Universität Zürich [Zürich] = University of Zurich (UZH), Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire d'Hématologie, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Hématopoïèse normale et pathologique (U1170 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Images et Modèles, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique des tumeurs (U985), Institut Gustave Roussy (IGR)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Chimie Moléculaire (SCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), 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, Plateforme de génomique, 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), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bases fondamentales et stratégies nouvelles en cancérologie (BFSNC - IFR54), 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 Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], CEA Direction des Sciences du Vivant (CEA/DSV), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University of Zurich, Mercher, Thomas, Gerby, Bastien, Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital Armand-Trousseau [Paris], University of Zürich [Zürich] (UZH), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Oncogene Proteins, Fusion, [SDV]Life Sciences [q-bio], Kaplan-Meier Estimate, Mice, SCID, Bioinformatics, Fusion gene, Mice, Acute megakaryoblastic leukemia, 0302 clinical medicine, Aurora Kinases, Leukemia, Megakaryoblastic, Acute, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Immunology and Allergy, ComputingMilieux_MISCELLANEOUS, Aurora Kinase A, Oligonucleotide Array Sequence Analysis, 0303 health sciences, High-Throughput Nucleotide Sequencing, GATA1, Azepines, Genomics, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Leukemia, 030220 oncology & carcinogenesis, 2723 Immunology and Allergy, Female, Molecular Sequence Data, Immunology, Kruppel-Like Transcription Factors, Aurora A kinase, 610 Medicine & health, [SDV.CAN]Life Sciences [q-bio]/Cancer, Protein Serine-Threonine Kinases, Biology, Article, 03 medical and health sciences, Chromosome 16, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Animals, Humans, Amino Acid Sequence, Gene, Aged, 030304 developmental biology, 2403 Immunology, Base Sequence, Gene Expression Profiling, Infant, medicine.disease, Xenograft Model Antitumor Assays, Repressor Proteins, Gene expression profiling, Pyrimidines, 10036 Medical Clinic, Cancer research
Abstract

A CBFA2T3-GLIS2 fusion gene was identified in 31% of non–Down syndrome AMKL., Acute megakaryoblastic leukemia (AMKL) is a heterogeneous disease generally associated with poor prognosis. Gene expression profiles indicate the existence of distinct molecular subgroups, and several genetic alterations have been characterized in the past years, including the t(1;22)(p13;q13) and the trisomy 21 associated with GATA1 mutations. However, the majority of patients do not present with known mutations, and the limited access to primary patient leukemic cells impedes the efficient development of novel therapeutic strategies. In this study, using a xenotransplantation approach, we have modeled human pediatric AMKL in immunodeficient mice. Analysis of high-throughput RNA sequencing identified recurrent fusion genes defining new molecular subgroups. One subgroup of patients presented with MLL or NUP98 fusion genes leading to up-regulation of the HOX A cluster genes. A novel CBFA2T3-GLIS2 fusion gene resulting from a cryptic inversion of chromosome 16 was identified in another subgroup of 31% of non–Down syndrome AMKL and strongly associated with a gene expression signature of Hedgehog pathway activation. These molecular data provide useful markers for the diagnosis and follow up of patients. Finally, we show that AMKL xenograft models constitute a relevant in vivo preclinical screening platform to validate the efficacy of novel therapies such as Aurora A kinase inhibitors.

Published
2012

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