Genomic instability and stem cell attrition as a preleukemia condition

Summary: Dr. Jean Soulier will discuss clonal hematopoiesis in Fanconi anemia (FA), a chromosome instability disorder with hematopoietic stem cell (HSC) exhaustion and propensity to myeloid leukemia. While it is known that spontaneous genetic reversion can rescue hematopoiesis, many other FA patients will develop clonal hematopoiesis related to chromosome 1q gain with resulting MDM4 trisomy that downregulates overactive p53 signaling. MDM4 triplication confers greater fitness to murine and human hematopoiesis, rescues inflammatory marrow failure, and drives clonal dominance in several mouse models. He will show at the single cell level how clonal hematopoiesis precedes secondary leukemia-driver alterations and FA transformation.

Biography: Jean Soulier is professor of hematology at the University Paris Cité and physician scientist at Saint-Louis Hospital where he heads the Hematology diagnosis lab and the Hematology research Unit. His translational research team aims to understand the pathogenesis of bone marrow failure syndromes and subsequent evolution towards clonal hematopoiesis and secondary leukemia (MDS/AML), including in patients with Fanconi anemia. This involves biological pathways of genome integrity, inflammation, aging, stem cell homeostasis and oncogenesis. Main approaches of the team are genomics on primary samples, and in vitro and in vivo modelling using experimental hematology systems. The research informs on mechanisms of normal and dysfunctional hematopoiesis, leukemia predisposition, patient diagnosis/staging and adapted therapeutics strategies.