Sustained PRC1.1 activity preserves gene repression independently of PRC2.2 and restrains leukemic cell differentiation
Fatemeh Mojallali et al.
Loss-of-function mutations in BCOR, a subunit of the non-canonical Polycomb Repressive Complex 1.1 (PRC1.1), are frequently observed in acute myeloid leukemia (AML) and associate with adverse risk. Paradoxically, leukemic stem cell viability in BCOR wild-type AMLs strongly depends on PRC1.1 activity. Here, we use BCOR and KDM2B degron models to study PRC1.1 dependency in leukemic cells and find that BCOR is a bridging factor tethering the catalytic and chromatin-binding moieties of the PRC1.1 complex. BCOR degradation induces a quick localized loss of H2AK119ub at PRC1.1 target genes, whereas PRC2-induced H3K27me3 remains unaffected. Degron-mediated depletion of BCOR or KDM2B induces a rapid but time-dependent transcriptional induction, whereby late-upregulated genes are more heavily decorated with H3K27me3 compared to early-upregulated genes. Combined PRC1.1 inactivation and PRC2 inhibition further amplifies gene induction, suggesting collaborative yet distinct control over target genes. Strikingly, both JARID2/AEBP2 and SUZ12 knockout cells, devoid of PRC2.2 or PRC2.1/PRC2.2 respectively, retain PRC1.1 loss-induced transcriptional activation, underscoring that PRC1.1 can repress target genes independently of a downstream PRC2.2-canonical PRC1 repressive axis. Finally, combined targeting of PRC1.1 and PRC2 induces differentiation of leukemic cells, emphasizing that co-targeting PRC1.1 and PRC2 represents a promising strategy to improve treatment of AML patients.
