Sustained PRC1.1 activity preserves gene repression independent of PRC2.2 and suppresses leukemic cell differentiation

ABSTRACT: Loss-of-function mutations in BCOR, 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, but underlying mechanisms driving leukemogenesis remain elusive. Here, we find that BCOR is a bridging factor tethering the catalytic and chromatin-binding moieties of the PRC1.1 complex. Degron-mediated depletion of BCOR or KDM2B induces a rapid but time-dependent transcriptional induction, whereby early-upregulated genes have a distinct epigenetic profile compared to late-upregulated genes that are more heavily decorated with H3K27me3. Combined KDM2B degradation and PRC2 inhibition further amplifies gene induction suggesting distinct yet collaborative control over target genes. Strikingly, both JARID2/AEBP2 and SUZ12 knockout cells, completely devoid of PRC2 functionality, retain PRC1.1-loss induced transcriptional activation, underscoring that PRC1.1 can repress target genes independent 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

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Leukocyte

DISEASE(S): Acute Leukemia

SUBMITTER: Justina Clarinda Wolters  

LAB HEAD: Dr. Justina Clarinda Wolters

PROVIDER: PXD065157 | Pride | 2026-06-15

REPOSITORIES: Pride