Molecular Dynamics of Hematopoietic Transformation

Objectives and Challenges

The team studies the fundamental mechanisms underlying human hematologic malignancies, focusing on acute myeloid leukemia (AML) and mature B-cell tumors such as Waldenström’s disease (WM) and diffuse large B-cell lymphoma (DLBCL). This research aims to understand how epigenetic regulators and transcription factors contribute to hematopoietic transformation, clonal evolution, and therapeutic resistance.

Research Areas/Major Projects

In the field of myeloid neoplasms (Virginie Penard-Lacronique), current projects explore the effects of mutations affecting IDH genes on metabolism and epigenetic processes, by studying the consequences of these abnormalities on metabolic remodeling and gene expression. The team is also developing expertise on a ribosomopathy, Diamond-Blackfan anemia, in the group led by Lydie Da Costa. Research on histiocytic neoplasms is helping to deepen our understanding of the consequences of RAS pathway activation (Jean-François Emile). In the field of lymphoid hematologic disorders, studies focus on the intrinsic plasticity of germinal center B cells, which underlie MW and LDGCB (Laurianne Scourzic). Molecular mechanisms are analyzed using integrative approaches that include iPS cell models and mouse models, through genomic, transcriptional, epigenetic, and immunophenotypic profiling (Olivier Bernard). The team is implementing high-throughput and single-cell analyses, as well as integrative biology, to identify biomarkers, in close collaboration with clinicians (Department of Hematology led by Stéphane de Botton) and bioinformaticians.

Major Findings and Scientific, Clinical, and Societal Impacts

The team contributed to the identification of the TET2 gene and to the study of the consequences of early mutations in this gene in myeloid hematologic malignancies and lymphomas. The team participated in studies examining the functional consequences of IDH mutant forms in AML and in the investigation of mechanisms of resistance to IDH inhibitors. Collaborations with clinicians and industry partners have enabled the team to participate in innovative clinical trials and identify biomarkers of treatment response. The team is now focused on deepening our understanding of tumor evolution and treatment resistance, while accelerating the translation of these discoveries into precision medicine.