PROJECT SUMMARY

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal diseases of mutated hematopoietic stem and progenitor cells (HSPC). Genes encoding components of the cohesin complex, including STAG2, SMC3 and RAD21, are frequently mutated in hematologic and solid malignancies, including 10-20% of MDS and secondary acute myeloid leukemia (AML), and they serve as predictors of poor outcomes. The biology of cohesin-mutant MDS/AML is not well understood and there are currently no cohesin-specific therapies available. Using human cell lines and patient samples that carry mutations in the cohesin complex, we have recently shown that cohesin-mutant cells have high expression of inflammatory genes and accumulation of Rloops. In this proposal, we will examine the role of R-loops as oncogenic enhancers using our genetically engineered mouse models of cohesin-mutant MDS. Furthermore, using both human and mouse models, we will investigate whether R-loop derived enhancer activity is a driver of these inflammatory changes. Improved understanding of the mechanisms by which cohesin mutations drive clonal expansion and progression from clonal hematopoiesis to MDS/AML has the potential to deliver novel therapeutic approaches for patients with these aggressive hematologic malignancies.