Research teams

We aim to address biological mechanisms of B to plasma cell development, tumorigenesis, progression and relapse, taking advantage of cellular models developed in the laboratory, (i) an in vitro memory B to plasma cell differentiation model which enable to address the mechanisms of tumorigenesis related to cyclic re-activation of memory B cells (Kassambara et al. Leukemia 2021; Alaterre E, Blood 2024); (ii) a large collection of longitudinal primary samples from patients (HEMODIAG cohort: http://www.chu-montpellier.fr/fr/hemodiag/projet/); and (iii) a large collection of lymphoma and MM cell lines (Vikova V, Theranostics 2019; Alaterre E, Theranostics 2022). To conduct the research, we will take advantage of the HEMODIAG cohort, longitudinal biobanking, high-quality annotations and strong collaboration with the department of clinical hematology to implement translational and basic research and develop therapeutic strategies. These projects will benefit from the SIRIC Montpellier, and Carnot CALYM programs and from an international network. We are using proprietary cellular models, large cohorts of samples, innovative genomic approaches and benefit from the invaluable support of Andrea Romero, Matthieu Abouladze, Ouissem Gadacha, Dassou Sika, Jean Luc Veyrune, Nicolas Robert and Guilhem Requirand.

Characterization of the 3D genome organization in MM cells and comparison with normal B to plasma cell differentiation stages.
Sara Ovejero, Laura Alibert, Matthieu Angles
In collaboration with the group of Giacomo Cavalli, our aim is to characterize the 3D features associated with myelomagenesis, in order to unravel the molecular mechanisms involved in the pathophysiology and help design new therapies. These data will be analyzed in combination to those from AID localization and will be compared to recurrent genomic abnormalities identified in MM, in order to determine whether the 3D chromatin organization and spatial co-localization during normal PC differentiation are related to the translocations and copy number alterations observed in MM.

Oncogenic addiction and therapeutic strategies to target MM cells and progenitors.
 Caroline Bret, Malik Lutzmann, Sara Ovejero, Morgane Thomas, Elvira Garcia De Paco
B lymphocytes are continuously produced during adult life and undergo genetic rearrangements during their maturation, including VDJ recombination, immunoglobulin (Ig) class switch recombination (CSR), and somatic hypermutation (SHM). Secondary lymphoid organs can also harbor a variety of oncogenic events that, depending on their mechanistic, can initiate the oncogenic transformation associated with multiple myeloma (MM) or diffuse large-cell B lymphoma (DLBCL) of the ABC type (activated B cells). During early tumorigenesis, founder mutations acquired by memory B cells (MBCs) as SHM off-targets or DNA replication errors following B cell activation, can produce a set of aberrant memory B cells that progressively outcompete wild-type memory B and naïve B cells during their clonal expansion. Using our in vitro memory B cell to PC differentiation model, we aim to develop CRISPR-CAS9 screen to better understand the molecular events involved in myelomagenesis, with a focus on genomic instability, stress related to immunoglobulin secretion, replication and epigenetic deregulation. We anticipate that this project will improve our understanding of oncogenic Achilles’ heels to target MM cells and progenitors.

Crosstalk between epitranscriptomic and epigenetic mechanisms in gene regulation during B to PC differentiation and B cell malignancies.
Charles Herbaux, Caroline Molinaro, Caroline Bret, Morgane Thomas
Recent technological advances have made it possible to gain evidence of a wide range of post-transcriptional RNA modifications that play pivotal and complementary roles in the regulation of fundamental biological processes including gene expression, a field of study collectively known as epitranscriptomics. During maturation, RNA becomes the substrate of various enzymes that can introduce chemical modifications into ribonucleotide residues. Altogether, these RNA modifications represent a new layer of control of genetic information and can affect a variety of molecular processes, thus indicating the regulation of RNA modification as a crucial step in the tight regulation of gene expression, mRNA stability, processing, and translation efficiency We aim to identify and understand the epitranscriptomic modifications during B to plasma cell differentiation, myelomagenesis and disease progression. We aim to characterize the biological functions of the enzymes involved in this epitranscriptomic remodeling and decrypt the crosstalk between RNA modification and epigenetic mechanisms. We will combine the use of normal plasma cell differentiation model and primary samples from patients, large cell lines collection, mass spectrometry-based RNA mark quantification, RNA modification profiles and ChIP-seq to monitor the evolution of the epitranscriptome and the crosstalk between epitranscriptomic and epigenetic changes in normal and malignant B cells in order to identify the downstream transcriptional impact and define new therapeutic approaches.

Define metabolic vulnerabilities in Multiple Myeloma.
Sara Ovejero, Caroline Bret, Elvira Garcia de Paco
Plasma cell tumorigenesis results in Multiple Myeloma (MM), a neoplasia characterized by the accumulation of clonal plasma cells within the bone marrow. Recent advances in treatment with the approval of several novel agents and their combinations have significantly improved patient outcome¹. However, patients invariably relapse after multiple lines of treatment, with shortened intervals between relapses, and finally become resistant to all treatments, resulting in loss of clinical control over the disease. In this proposal, we seek to determine how metabolic alterations during the differentiation of normal B cells into plasma cells contribute to the development of MM, and what metabolomic signatures can be identified that correlate with drug resistance and disease progression. We would like to reveal both the pathways involved in this metabolic remodeling and their downstream effects. The rationale of our project is in line with the identification of major metabolic changes during plasma cell differentiation and in MM cells in association with drug resistance and poor outcome.

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• Miglierina E, Bouder J, Ordanoska D, Pineau M, Léonard S, Schavgoulidze A, Quéré G, Le Goff M, Bouchet M, Genebrier SA, Trinca SBS, Deleurme L, Monvoisin C, Derrier L, Dumontet C, Delpy L, Moreaux J, Corre J, Cogné M, Laffleur B. DIS3 licenses B cells for plasma cell differentiation in humans. Cell Mol Immunol. 2026 Jan;23(1):31-47.
• Ovejero S, Devin J, Alibert L, Soun C, Lin YL, Dutrieux L, Abouladze M, Garcia de Paco E, Karmous Gadacha O, Constantinou A, Cartron G, Herbaux C, Elemento O, Pasero P, Roulland S, Moreaux JC, Bret CC. Synthetic Lethal Combinations of DNA Repair Inhibitors and Genotoxic Agents to Target High-Risk Diffuse Large B. Cell Lymphoma. Hematol Oncol. 2025 Sep;43(5):e70131.
• Jacquier V, Romero A, Molinaro C, Somayaji R, Abouladze M, Gadacha OK, Ovejero S, de Boussac H, Gabellier L, Davids MS, Moreaux J, Herbaux C. Development of a robust BH3 drug toolkit for precision medicine in hematologic malignancies. Theranostics. 2025 Apr 21;15(12):5705-5718.
• Cahen M, Léonard J, Dézé O, Deleurme L, Pineau M, Tanguy AL, Paul S, Moreaux J, Noël G, Ueda N, Danger Y, Cogné M. Editing B cells at the IGHA2 gene position provides alternative route to therapeutic IgA production. Mucosal Immunol. 2025 Oct;18(5):1027-1035.
• Chemlal D, Pochard C, Jacquier V, Bruyer A, Gabellier L, Fornero L, Vempère C, Machura A, Requirand G, Robert N, Bret C, Cartron G, Vincent L, de Boussac H, Moreaux JC, Herbaux CC. CD200 immune checkpoint expression is associated with inferior outcome in multiple myeloma patients treated with anti-CD38 monoclonal antibodies. Oncoimmunology. 2025 Dec;14(1):2532226.
• Ovejero S*, Alibert L*, Devin J, Caneque T, Jacquier V, Romero A, Amar S, Abouladze M, Garcia De Paco E, Karmous Gadacha O, Requirand G, Robert N, Zellagui ML, De Boussac H, Cartron G, Chiche J, Ricci JE, Herbaux C, Rodriguez R, Moreaux JC, Bret CC. Ironomycin induces mantle cell lymphoma cell death by targeting iron metabolism addiction. Theranostics. 2025.
• Dutrieux L, Ovejero S, Guillemin A, Zellagui L, De Bruyne E, Muylaert C, Van Hemelrijck L, Lin YL, Loughran E, Choquet A, Magat T, Bouchouika S, Bret C, Requirand G, Robert N, Vincent L, Cartron G, Herbaux C, Rodriguez R, Cogné M, Rivals E, Andrau JC, David A, Pasero P and Moreaux JC (2024) Targeting Transcription-Replication Conflicts using G-quadruplexes stabilizers in Multiple Myeloma. Blood Neoplasia, 2025 Jan 20;2(2):100072.
• Alaterre E*, Ovejero S*, Bret C, Dutrieux L, Sika D, Fernandez Perez R, Espéli M, Fest T, Cogné M, Martin-Subero JI, Milpied P, Cavalli G, Moreaux JC. Integrative single-cell chromatin and transcriptome analysis of human plasma cell differentiation. Blood. 2024 Aug 1;144(5):496-509.
• Constantinides M, Robert N, Multrier C, Coënon L, Campos-Mora M, Jacquard C, Gao F, Zemiti S, Presumey J, Cartron G, Moreaux JC*, Villalba MC*. FCGR3A F158V alleles frequency differs in multiple myeloma patients from healthy population. Oncoimmunology. 2024 Aug 18;13(1):2388306.
• Chemlal D*, Varlet E*, Machura A, Ovejero S, Requirand G, Robert N, Cartron G, Alaterre E, Bret C, Vincent L, Herbaux C, Cavalli G, Bruyer A, De Boussac H, Moreaux JC. EZH2 targeting induces CD38 upregulation and response to anti-CD38 immunotherapies in multiple myeloma. Leukemia. 2023 Sep;37(9):1925-1928.
• Devin J, Cañeque T, Lin YL, Mondoulet L, Veyrune JL, Abouladze M, Garcia De Paco E, Karmous Gadacha O, Cartron G, Pasero P, Bret CC*, Rodriguez RC* and Moreaux JC*. * Equal contribution. Targeting cellular iron homeostasis with ironomycin in diffuse large B cell lymphoma. Cancer Research. 2022. Jan 25:canres.0218.2021.
• Alaterre E, Ovejero S, Herviou L, De Boussac H, Papadopoulos G, Kulis M, Boireau S, Robert N, Requirand G, Bruyer A, Cartron G, Vincent L, Martinez AM, Martin-Subero JI, Cavalli G and Moreaux JC. Comprehensive characterization of the epigenetic landscape in Multiple Myeloma. Theranostics 2022 Jan 16;12(4):1715-1729.
• Kassambara A, Herviou L, Ovejero S, Jourdan M, Thibaut C, Vikova V, Pasero P, Elemento O, Moreaux JC. RNA sequencing data-driven dissection of human plasma cell differentiation reveals new potential transcription regulators. Leukemia. 2021; 35, 1451-1462.
• De Smedt E*, Devin J*, Muylaert C, Robert N, Requirand G, Vlummens P, Vincent L, Cartron G, Maes K, Moreaux JC and De Bruyne EC. G9a/GLP-targeting in MM promotes autophagy-associated apoptosis and boosts proteasome inhibitor mediated cell death. Blood Advances. 2021; 5, 2325-2338.
• De Boussac H, Bruyer A, Jourdan M, Maes A, Robert N, Gourzones C, Vincent L, Seckinger A, Cartron G, Hose D, De Bruyne E, Kassambara A, Pasero P, Moreaux JC. Kinome expression profiling to target new therapeutic avenues in Multiple Myeloma. Haematologica. 2020 Mar;105(3):784-795.
• Chatonnet F, Pignarre A, Sérandour AA, Caron G, Avner S, Robert N, Kassambara A, Laurent A, Bizot M, Agirre X, Prosper F, Martin-Subero JI, Moreaux JC*, Fest TC*, Salbert GC*. The hydroxymethylome of multiple myeloma identifies FAM72D as a 1q21 marker linked to proliferation. Haematologica. 2020 Mar;105(3):774-783.
• Vikova V, Jourdan M, Robert N, Requirand G, Boireau S, Bruyer A, Vincent L, Cartron G, Klein B, Elemento O, Kassambara A, Moreaux JC. Comprehensive characterization of the mutational landscape in multiple myeloma cell lines reveals potential drivers and pathways associated with tumor progression and drug resistance. Theranostics. 2019; 9(2): 540-553.
• Coquel F, Ho SZ, Tsai KC, Yang CY, Aze A, Devin J, Chang TH, Kong-Hap M, Bioteau A, Moreaux J, Maiorano D, Pourquier P, Yang WC, Lin YLC, Pasero PC. Synergistic effect of inhibiting CHK2 and DNA replication on cancer cell growth. Elife. 2025 Jan 31;13:RP104718.
• Haas M, Cherfa S, Nguyen L, Bourgoin M, Caron G, Dessauge E, Marchand T, Delpy L, Auberger P, Moreaux J, Jacquel A, Fest TC. PIM2 inhibition promotes MCL1 dependency in plasma cells involving integrated stress response-driven NOXA expression. Nat Commun. 2025 Jan 2;16(1):256.
• Moreaux JC. KDM6A controls immunogenicity in MM. Blood. 2024 Oct 3;144(14):1465-1467.
• Ueda N, Cahen M, Leonard J, Deleurme L, Dreano S, Sirac C, Galy A, Moreaux J, Danger Y, Cogné MC. Single-hit genome editing optimized for maturation in B cells redirects their specificity toward tumor antigens. Sci Rep. 2024 Sep 28;14(1):22432.
• Técher H, Gopaul D, Heuzé J, Bouzalmad N, Leray B, Vernet A, Mettling C, Moreaux J, Pasero PC, Lin YLC. MRE11 and TREX1 control senescence by coordinating replication stress and interferon signaling. Nat Commun. 2024 Jun 26;15(1):5423.
• Parreno V, Loubiere V, Schuettengruber B, Fritsch L, Rawal CC, Erokhin M, Győrffy B, Normanno D, Di Stefano M, Moreaux J, Butova NL, Chiolo I, Chetverina D, Martinez AM, Cavalli GC. Transient loss of Polycomb components induces an epigenetic cancer fate. Nature. 2024 May;629(8012):688-696.
• Massoni-Badosa R, Aguilar-Fernández S, Nieto JC, Soler-Vila P, Elosua-Bayes M, Marchese D, Kulis M, Vilas-Zornoza A, Bühler MM, Rashmi S, Alsinet C, Caratù G, Moutinho C, Ruiz S, Lorden P, Lunazzi G, Colomer D, Frigola G, Blevins W, Romero-Rivero L, Jiménez-Martínez V, Vidal A, Mateos-Jaimez J, Maiques-Diaz A, Ovejero S, Moreaux J, Palomino S, Gomez-Cabrero D, Agirre X, Weniger MA, King HW, Garner LC, Marini F, Cervera-Paz FJ, Baptista PM, Vilaseca I, Rosales C, Ruiz-Gaspà S, Talks B, Sidhpura K, Pascual-Reguant A, Hauser AE, Haniffa M, Prosper F, Küppers R, Gut IG, Campo E, Martin-Subero JIC, Heyn HC. An atlas of cells in the human tonsil. Immunity. 2024 Feb 13;57(2):379-399.e18.
• Haas M, Caron G, Chatonnet F, Manenti S, Alaterre E, Devin J, Delaloy C, Bertolin G, Viel R, Pignarre A, Llamas Gutierrez F, Marchalot A, Decaux O, Tarte K, Delpy L, Moreaux J, Fest TC. Pivotal role of PIM2 kinase in plasmablast generation and plasma cell survival, opening new treatment options in myeloma. Blood. 2022 Feb 2:blood.2021014011.
• Moreaux J. The origin of preplasmablastic cells. Blood. 2021 Mar 4;137(9):1134-1135.
• 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 DAC. Discovery of Candidate DNA Methylation Cancer Driver Genes. Cancer Discov. 2021 May 10.