Deconstructing Niche Contributions to Leukemogenesis: Modeling Shwachman-Diamond Syndrome

Hematopoietic stem and progenitor cells (HSPC) proliferate and differentiate to provide a lifelong production of blood cells, but sustained proliferation puts them at risk of accumulating genetic mutations associated with human leukemia. Genetically-engineered mouse models have shown that an aberrant HSPC microenvironment (niche) can promote leukemogenesis, but the underlying molecular mechanisms and their relevance to human disease remained to be elucidated. This thesis investigates these key issues in mouse models of Shwachman-Diamond syndrome (SDS), a human bone marrow failure and leukemia predisposition disorder caused by loss-of-function mutations in the gene Sbds. Mice with hematopoietic cell-restricted Sbds deficiency developed bone marrow failure but not leukemia, suggesting that non-hematopoietic cells may contribute to malignant transformation of HSPCs in SDS. Conversely, HSPCs from mice with niche cell-confined Sbds deficiency presented oxidative stress and DNA damage, revealing a novel concept of niche-induced genotoxic stress in HSPCs, relevant for mutation accrual and leukemogenesis in SDS. S100A8 and SlOOA9 were identified as candidate niche factors driving HSPC genotoxicity. High niche S100A8/9 expression predicted poor outcome in low-risk myelodysplastic syndrome (MDS), independently of known prognostic factors. Profiling low-risk MOS niche cells revealed DNA damage, cellular stress and inflammatory pathway activation, which will be tested as underlying S100A8/9 overexpression in the MDS microenvironment.
This thesis identified niche contributions to HSPC genomic instability in pre leukemic conditions and verified the relevance of this concept for human disease. Future analyses will determine whether niche contributions are necessary for leukemogenesis, raising the perspective of microenvironment-instructed therapeutic strategies to delay or prevent leukemogenesis.