GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE286nnn/GSE286991/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE286991GEOGSEfalseSustained PRC1.1 activity preserves gene repression independently of PRC2.2 and restrains leukemic cell differentiationLoss-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.2026/06/12GSE286991GSM9543144GSM9543146GSM9543145GSM9543148GSM9543147GSM9543149GSM8735801GSM8735800GSM8735844GSM8735843GSM8735842GSM8735841GSM8735840GSM8735809GSM8735808GSM8735807GSM8735806GSM8735805GSM8735804GSM8735803GSM8735802GSM8735793GSM8735792GSM8735791GSM8735790GSM8735834GSM8735833GSM8735832GSM8735799GSM8735798GSM8735831GSM8735797GSM8735830GSM8735796GSM8735795GSM8735794GSM8735839GSM8735838GSM8735837GSM8735836GSM8735835GSM9543162GSM9543161GSM9543164GSM9543163GSM9543166GSM9543165GSM9543167GSM8735782GSM8735781GSM8735780GSM8735823GSM8735789GSM8735822GSM8735821GSM8735788GSM8735820GSM8735787GSM8735786GSM8735785GSM8735784GSM8735783GSM8735829GSM8735828GSM8735827GSM8735826GSM9543160GSM8735825GSM8735824GSM9543151GSM9543150GSM9543153GSM9543152GSM9543155GSM9543154GSM9543157GSM9543156GSM9543159GSM9543158GSM8735812GSM8735779GSM8735778GSM8735811GSM8735777GSM8735810GSM8735776GSM8735775GSM8735774GSM8735773GSM8735819GSM8735818GSM8735817GSM8735816GSM8735815GSM8735814GSM87358131857334284286991Homo sapiens[42273916]