|Publication Type||Journal Article|
|Year of Publication||2022|
|Authors||Schaefer, EJ, Wang, HC, Karp, HQ, Meyer, CA, Cejas, P, Gearhart, MD, Adelman, ER, Fares, I, Apffel, A, Lim, K, Xie, Y, Gibson, CJ, Schenone, M, H Murdock, M, Wang, ES, Gondek, LP, Carroll, MP, Vedula, RS, Winer, ES, Garcia, JS, Stone, RM, Luskin, MR, Carr, SA, Long, HW, Bardwell, VJ, Figueroa, ME, R Lindsley, C|
|Journal||Blood Cancer Discov|
|Date Published||2022 Mar 01|
Polycomb repressive epigenetic complexes are recurrently dysregulated in cancer. Unlike polycomb repressive complex 2 (PRC2), the role of PRC1 in oncogenesis and therapy resistance is not well-defined. Here, we demonstrate that highly recurrent mutations of the PRC1 subunits BCOR and BCORL1 in leukemia disrupt assembly of a noncanonical PRC1.1 complex, thereby selectively unlinking the RING-PCGF enzymatic core from the chromatin-targeting auxiliary subcomplex. As a result, BCOR-mutated PRC1.1 is localized to chromatin but lacks repressive activity, leading to epigenetic reprogramming and transcriptional activation at target loci. We define a set of functional targets that drive aberrant oncogenic signaling programs in PRC1.1-mutated cells and primary patient samples. Activation of these PRC1.1 targets in BCOR-mutated cells confers acquired resistance to treatment while sensitizing to targeted kinase inhibition. Our study thus reveals a novel epigenetic mechanism that explains PRC1.1 tumor-suppressive activity and identifies a therapeutic strategy in PRC1.1-mutated cancer.
SIGNIFICANCE: We demonstrate that BCOR and BCORL1 mutations in leukemia unlink PRC1.1 repressive function from target genes, resulting in epigenetic reprogramming and activation of aberrant cell signaling programs that mediate treatment resistance. Our study provides mechanistic insights into the pathogenesis of PRC1.1-mutated leukemia that inform novel therapeutic approaches. This article is highlighted in the In This Issue feature, p. 85.
|Alternate Journal||Blood Cancer Discov|
|Grant List||K08 CA204734 / CA / NCI NIH HHS / United States |
T32 HL116324 / HL / NHLBI NIH HHS / United States
DFG-SCHA2121/1-1 / / Edward P. Evans Foundation /
K08CA204734 / GF / NIH HHS / United States