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Blood Cancer Discov DOI:10.1158/2643-3230.BCD-21-0115

BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes.

Publication TypeJournal Article
Year of Publication2022
AuthorsSchaefer, 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
JournalBlood Cancer Discov
Volume3
Issue2
Pages116-135
Date Published2022 Mar 01
ISSN2643-3249
Abstract

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.

DOI10.1158/2643-3230.BCD-21-0115
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/35015684?dopt=Abstract

Alternate JournalBlood Cancer Discov
PubMed ID35015684
Grant ListK08 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