Epigenome modifications and genomic instability in normal and malignant B cells

Molecular bases of human diseases

Antibody secreting cells are critical effector cells and long-lived sentinels for immune memory. B cell maturation should be tightly regulated to ensure efficient immune response without autoimmunity or immune deficiency. On the transcriptional level, the differentiation of B cells into plasma cells is associated with substantial and coordinated changes in the gene expression profile, which fall into two main categories: the loss of B cell-associated transcripts and the acquisition of plasma cell gene expression program. These changes are tightly guided by two sets of stage-specific transcription factors (TFs) that repress each other: i) B cell TFs (PAX5, BCL6 and BACH2) maintaining the B cell fate and ii) plasma cell TFs (IRF4, BLIMP1 and XBP1) that are required to extinguish the B cell genes and activate the antibody-secreting cell program. Although the role of the complex network of transcription factors involved in plasma cell differentiation has been investigated, the mechanisms regulating key plasma cell differentiation transcription networks remain poorly known. Little is known about the dynamic and hierarchical nuclear architecture in B to plasma cell differentiation and how it could regulate fundamental processes during normal plasma cell differentiation. We aim to characterize and understand the epigenetic, remodeling, structural and architectural changes that affect chromatin during B to plasma cell differentiation. Furthermore, we aim to identify the molecular events involved in tumorigenesis during B to PC differentiation.

Mature B cell malignancies are genetically and clinically heterogeneous diseases. Treatment improvements will come from a better comprehension of tumorigenesis and detailed molecular analyses to develop individualized therapies that take into account their molecular heterogeneity and subclonal evolution.

Our laboratory uses genome data, computing, mathematical modeling and unique cellular models to study mature B cells and plasma cells with a focus on epigenome modifications and genomic instability. These approaches work in tandem with technological advancements to study tumorigenesis and to understand the mechanisms of tumor progression and drug resistance to develop new diagnostic and treatment strategies.

These projects are developed in collaboration with other groups of the IGH together with the departments of biological and clinical hematology of the university hospital of Montpellier. Taking advantage of the link with the laboratory of monitoring innovative therapies (Montpellier University Hospital), dedicated to diagnosis and residual disease monitoring of patients with plasma cell neoplasms, we aim to strongly foster a transformation of basic research into translational and clinical applications.

We created a startup company Diag2Tec to valorize the research activity of the group.

PUBLICATIONS OF THE TEAM

Discovery of candidate DNA methylation cancer driver genes.

Pan H, Renaud L, Chaligne R, Bloehdorn J, Tausch E, Mertens D, Fink AM, Fischer K, Zhang C, Betel D, Gnirke A, Imielinski M, Moreaux J, Hallek M, Meissner A, Stilgenbauer S, Wu CJ, Elemento O, Landau DA

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Multi-omics tumor profiling technologies to develop precision medicine in multiple myeloma

Sara Ovejero, Jerome Moreaux

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DNA Repair Expression Profiling to Identify High-Risk Cytogenetically Normal Acute Myeloid Leukemia and Define New Therapeutic Targets

Ludovic Gabellier, Caroline Bret, Guillaume Bossis, Guillaume Cartron and Jérôme Moreaux

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Kinome expression profiling to target new therapeutic avenues in multiple myeloma

Hugues de Boussac Angélique Bruyer Michel Jourdan Anke Maes Nicolas Robert Claire Gourzones Laure Vincent Anja Seckinger Guillaume Cartron Dirk Hose Elke De Bruyne Alboukadel Kassambara Philippe Pasero Jérôme Moreaux

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CD38 antibodies in multiple myeloma

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Treatment may be harmful : mechanisms/preduction/prevention of drug-induced DNA damage and repair in multiple myeloma

Claire Gourzones, Caroline Bret and Jerome Moreaux

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Phenotype Characterization of Diffuse Large B cell Lymphoma Cells and Prognostic Impact

Julie Devin, Alboukadel Kassambara, Angélique Bruyer, Jérôme Moreaux and Caroline Bret

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Antioxidant Defenses Confer Resistance to High Dose Melphalan in Multiple Myeloma Cells

Claire Gourzones, Céline Bellanger, Sylvain Lamure, Ouissem Karmous Gadacha, Elvira Garcia De Paco, Laure Vincent, Guillaume Cartron, Bernard Klein and Jérôme Moreau

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EZH2 is overexpressed in transitional preplasmablasts and is involved in human plasma cell differentiation

Laurie Herviou, Michel Jourdan, Anne-Marie Martinez, Giacomo Cavalli, Jerome Moreaux

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Comprehensive characterization of the mutational landscape in multiple myeloma cell lines reveals potential drivers and pathways associated with tumor progression and drug resistance

Veronika Vikova, Michel Jourdan, Nicolas Robert, Guilhem Requirand, Stéphanie Boireau, Angélique Bruyer, Laure Vincent, Guillaume Cartron, Bernard Klein, Olivier Elemento, Alboukadel Kassambara, Jérôme Moreaux

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BrdU incorporation in multiparameter flow cytometry: A new cell cycle assessment approach in multiple myeloma.

Requirand G, Robert N, Boireau S, Vincent L, Seckinger A, Bouhya S, Ceballos P, Cartron G, Hose D, Klein B, Moreaux J

PRC2 targeting is a therapeutic strategy for EZ score defined high-risk multiple myeloma patients and overcome resistance to IMiDs

Laurie Herviou, Alboukadel Kassambara, Stéphanie Boireau, Nicolas Robert, Guilhem Requirand, Carsten Müller-Tidow, Laure Vincent, Anja Seckinger, Hartmut Goldschmidt, Guillaume Cartron, Dirk Hose, Giacomo Cavalli & Jerome Moreaux

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An epigenetic regulator-related score (EpiScore) predicts survival in patients with diffuse large B cell lymphoma and identifies patients who may benefit from epigenetic therapy

Vanessa Szablewski, Caroline Bret, Alboukadel Kassambara, Julie Devin, Guillaume Cartron, Valérie Costes-Martineau and Jérôme Moreaux

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DNMTi/HDACi combined epigenetic targeted treatment induces reprogramming of myeloma cells in the direction of normal plasma cells

Angelique Bruyer, Ken Maes, Laurie Herviou, Alboukadel Kassambara, Anja Seckinger, Guillaume Cartron, Thierry Rème, Nicolas Robert, Guilhem Requirand, Stéphanie Boireau, Carsten Müller-Tidow, Jean-luc Veyrune, Laure Vincent, Salahedine Bouhya, Hartmut Goldschmidt, Karin Vanderkerken, Dirk Hose, Bernard Klein, Elke De Bruyne & Jerome Moreaux

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Combined inhibition of two bad prognosis genes: Chk1 and Wee1 as a new therapeutic strategy for Multiple Myeloma [Abstract]

Angélique Bruyer, Hugues de Boussac, Thibaut Martin, Alboukadel Kassambara, Nicolas Robert, Hose D, Anja Seckinger, Philippe Pasero, Jérôme Moreaux

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Combined inhibition of two bad prognosis genes: Chk1 and Wee1 as a new therapeutic strategy for Multiple Myeloma [Poster]

Angélique Bruyer, Hugues de Boussac, Thibaut Martin, Alboukadel Kassambara, Nicolas Robert, Hose D, Anja Seckinger, Philippe Pasero, Jérôme Moreaux

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CD24, CD27, CD36 and CD302 gene expression for outcome prediction in patients with multiple myeloma

Elina Alaterre, Sebastien Raimbault, Hartmut Goldschmidt, Salahedine Bouhya, Guilhem Requirand, Nicolas Robert, Stéphanie Boireau, Anja Seckinger, Dirk Hose, Bernard Klein and Jérôme Moreaux

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Automated and Simplified Identification of Normal and Abnormal Plasma Cells in Multiple Myeloma by Flow Cytometry

Elina Alaterre, Sebastien Raimbault, Jean-Michel Garcia,Thierry Reme,Guilhem Requirand, Bernard Klein, and Jerome Moreaux

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Hypoxia favors the generation of human plasma cells

Michel Jourdan, Angélique Bruyer, Alboukadel Kassambara, Bernard Klein & Jérôme Moreaux

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Global miRNA expression analysis identifies novel key regulators of plasma cell differentiation and malignant plasma cell

Alboukadel Kassambara, Michel Jourdan, Angelique Bruyer, Nicolas Robert, Veronique Pantesco, Olivier Elemento, Bernard Klein and Jerome Moreaux

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RECQ1 helicase is involved in replication stress survival and drug resistance in multiple myeloma

E Viziteu, B Klein, J Basbous, Y-L Lin, C Hirtz, C Gourzones, L Tiers, A Bruyer, L Vincent, C Grandmougin, A Seckinger, H Goldschmidt, A Constantinou, P Pasero, D Hose, J Moreaux

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Differential effects of lenalidomide during plasma cell differentiation

Michel Jourdan, Maïlys Cren, Peter Schafer, Nicolas Robert, Christophe Duperray, Laure Vincent, Patrice Ceballos, Guillaume Cartron, Jean-François Rossi, Jérôme Moreaux, Rajesh Chopra, Bernard Klein

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Identifying high-risk adult AML patients: epigenetic and genetic risk factors and their implications for therapy

Caroline Bret, Elena Viziteu, Alboukadel Kassambara & Jerome Moreaux

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Chetomin, targeting HIF-1a/p300 complex, exhibits antitumour activity in multiple myeloma

Elena Viziteu, Camille Grandmougin, Hartmut Goldschmidt, Anja Seckinger, Dirk Hose, Bernard Klein, Jerome Moreaux

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DNA repair in diffuse large B-cell lymphoma: a molecular portrait

Caroline Bret, Bernard Klein, Guillaume Cartron, Jean-François Schved, Angelos Constantinou, Philippe Pasero, Jérôme Moreaux

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EZH2 in normal hematopoiesis and hematological malignancies

Laurie Herviou, Giacomo Cavalli, Guillaume Cartron, Bernard Klein and Jérôme Moreaux

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GenomicScape : AnEasy-to-Use Web Tool for Gene Expression Data Analysis. Application to Investigate the Molecular Events in the Differentiation of B Cells into Plasma Cells

Alboukadel Kassambara, Thierry Rème, Michel Jourdan, Thierry Fest, Dirk Hose, Karin Tarte, Bernard Klein

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Gene expression-based prediction of myeloma cell sensitivity to histone deacetylase inhibitors

J Moreaux, T Reme, W Leonard, J-L Veyrune, G Requirand, H Goldschmidt, D Hose & B Klein

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Nucleotide excision DNA repair pathway as a therapeutic target in patients with high-risk diffuse large B cell lymphoma

Caroline Bret, Bernard Klein and Jérôme Moreaux

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Nucleotide excision DNA repair pathway as a therapeutic target in patients with high-risk diffuse large B cell lymphoma

Caroline Bret, Bernard Klein and Jérôme Moreaux

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Gene expression-based risk score in diffuse large B-cell lymphoma

Caroline Bret, Bernard Klein, and Jérôme Moreaux

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Development of gene expression-based risk score in cytogenetically normal acute myeloid leukemia patients

Elias Bou Samra, Bernard Klein, Thérèse Commes, and Jérôme Moreaux

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Development of gene expression based score to predict sensitivity of multiple myeloma cells to DNA methylation

Jérôme Moreaux, Thierry Rème, Wim Leonard, et al.

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Characterization of a Transitional Preplasmablast Population in the Process of Human B Cell to Plasma Cell Differentiation

Michel Jourdan, Anouk Caraux, Gersende Caron, Nicolas Robert, Geneviève Fiol, Thierry Rème, Karine Bolloré, Jean-Pierre Vendrell, Simon Le Gallou, Frédéric Mourcin, John De Vos, Alboukadel Kassambara, Christophe Duperray, Dirk Hose, Thierry Fest, Karin Tarte and Bernard Klein

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A high-risk signature for patients with multiple myeloma established from the molecular classification of human myeloma cell lines.

Moreaux J, Klein B, Bataille R, Descamps G, Maïga S, Hose D, Goldschmidt H, Jauch A, Rème T, Jourdan M, Amiot M, Pellat-Deceunynck C

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An in vitro model of differentiation of memory B cells into plasmablasts and plasma cells including detailed phenotypic and molecular characterization.

Jourdan M, Caraux A, De Vos J, Fiol G, Larroque M, Cognot C, Bret C, Duperray C, Hose D, Klein B

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Role of transcription/replication conflicts in myelomagenesis and development of new therapeutic approaches
by Laure Dutrieux under the supervision of Jérôme Moreaux
In preparation since 01-12-2020

Treatment of Multiple Myeloma by inhibition of Polycomb factors
by Emmanuel Varlet under the supervision of Jérôme Moreaux
In preparation since 30-09-2019