UMR 1287 - Hematopoietic stem cells and the development of myeloid malignancies
At the apex of the hematopoietic tissue, hematopoietic stem cells (HSCs) self-renew and give rise to all blood cell lineages. The tightly regulated mechanisms involved in normal hematopoiesis include a number of intrinsic factors, such as transcription factors & epigenetic marks, and extrinsic factors such as surrounding cells of the niche and the cytokines they produce.
The hematopoietic system is subjected to many changes throughout life. HSCs develop in discrete anatomical niches, migrating during embryogenesis from the aorta-gonad-mesonephros (AGM) region to the fetal liver, and finally to the bone marrow, where most HSCs reside throughout adult life. Unlike adult bone marrow HSCs, which are mostly quiescent, fetal liver HSCs are highly proliferative. Ontogenic changes are also occurring in different lineages. For example, in the megakaryocyte lineage, some observations suggest that embryonic and fetal MK and platelets may have specific properties and functions. Hereditary thrombocytopenia and MPNs could affect not only the adult hematopoiesis but also the embryonic/fetal hematopoiesis, including primitive hematopoiesis.
On the other side of the time scale, the aging hematopoietic system undergoes numerous changes, including increased myeloid cell counts and decreased adaptive immune response. Clonal abnormalities, so-called age-related clonal hematopoiesis (ARCH), can develop and create a preleukemic state. Aging of the hematopoietic tissue promotes the onset of myeloid malignancies such as myelodysplastic syndromes (SMD), MPNs and overlapping diseases. Phenotypic manifestations of normal and pathological hematopoietic aging might also reflect alterations in more differentiated hematopoietic cell types.
The research of the two groups of: “Hematopoietic stem cells and the development of myeloid malignancies” unit will be dedicated to fundamental and pathological aspects of HSC function and differentiation of the myelomonocytic (team 1) megakaryocytic (team 2) lineages. Our common aim is to understand how hematopoietic stem cell changes occurring throughout life contribute to the predisposition and the development of blood disorders affecting these lineages, with a particular focus on hereditary hemopathies and acquired myeloproliferative neoplasms (MPNs) or mix MPN/myelodysplastic syndromes such as Chronic myelomonocytic leukemia (CMML).
Four main research axes are developed in the two teams:
- Evaluate the epigenetic, molecular and cellular changes in HSCs, and the regulation of megakaryocyte and myelomonocytic lineages at different times during life: embryonic/fetal life, adulthood, advanced age.
- Understand how different myeloid neoplasms - with distinct phenotypes and prognoses - emerge from the same tissue and share the same genetic lesions.
- Decipher the changes occurring in the microenvironment and its role in the development of myeloproliferative neoplasms. Characterize the interaction of malignant clones with the microenvironment.
- Improve the diagnostic of patients at risk and discover new therapeutic approaches to treat these blood disorders.
This Research Unit is subdivided into two teams:
Team 1 : Françoise PORTEU, « Hematopoietic tissue aging »
Team 2 : Isabelle PLO & Hana RASLOVA, « From Hematopoietic stem cells to megakaryocytes »