Grant: CIHR Fellowship

Somatic mutations affecting components of the Polycomb repressive complexes (PRC) are present in >30% of patients with myelodysplastic syndromes (MDS), suggesting a powerful mechanistic link between regulation of the histone epigenetic code and MDS pathogenesis. BCOR is part of a variant PRC1 that coordinates chromatin remodeling and is recurrently mutated in MDS and secondary acute myeloid leukemia (s-AML). The mechanism by which BCOR mutations drive MDS pathogenesis is not understood. In preliminary studies using novel in vivo and in vitro models, we found that Bcor deficiency disrupts normal hematopoietic function and promotes key features of myeloid transformation, including enhanced stem cell self-renewal and sensitivity to activated RAS signaling. Moreover, we identified potent functional cooperativity between Bcor and Tet2 mutations. In this proposal, we will investigate the mechanistic basis for the oncogenic effects of somatic Bcor loss, and examine how genetic context modifies the functional consequences of Bcor inactivation in myeloid cells.