Aging of the Hematopoietic Tissue

Themes, Objectives, and Challenges

Our team studies the impact of aging on myeloid differentiation, from hematopoietic stem cells (HSCs) to mature cells: monocytes (MO), granulocytes (GRAN), and dendritic cells (DC). It analyzes the effects of intrinsic factors (genetic alterations, epigenetic dysregulation, transposable elements (TEs)) and extrinsic factors (bone marrow microenvironment, inflammation) in physiological, stress, and pathological contexts, using chronic myelomonocytic leukemia (CMML) as a model. Our goal is to understand the epigenetic mechanisms responsible for the aging of HSCs and to explore the progression of clonal hematopoiesis toward myeloid hematologic disorders. We are also studying the interactions between leukemic cells, HSCs, and the microenvironment to identify new biomarkers and therapeutic targets, integrating approaches from single-cell biology, mathematical modeling, and the philosophy of science to better understand clonal evolution.

Results, Prospects, and Scientific, Clinical, and Societal Impacts

Our work has shown that the disorganization of heterochromatin (H3K9me2/3) and the reactivation of transposable elements constitute a major mechanism underlying the functional decline of HSCs during aging. In LMMC, our work has led to the development of a diagnostic test based on monocyte distribution, which has been incorporated into the 2022 WHO classification. We have also demonstrated the role of mature leukemic clone cells in inflammation and disease progression, identified a defect in monocyte apoptosis, and proposed new therapeutic strategies targeting these cells and their cytokines. Ultimately, our research aims to identify modulable mechanisms to slow hematopoietic aging and to develop new treatments to prevent disease progression and transformation.