%0 Journal Article %A Eva J. Schaefer %A Helen C. Wang %A Clifford A. Meyer %A Paloma Cejas %A Micah D. Gearhart %A Emmalee R. Adelman %A Iman Fares %A Annie Apffel %A Klothilda Lim %A Yingtian Xie %A Christopher J. Gibson %A Monica Schenone %A H. Moses Murdock %A Eunice S. Wang %A Lukasz P. Gondek %A Martin P. Carroll %A Rahul S. Vedula %A Eric S. Winer %A Jacqueline S. Garcia %A Richard M. Stone %A Marlise R. Luskin %A Steven A. Carr %A Henry W. Long %A Vivian J. Bardwell %A Maria E. Figueroa %A R. Coleman Lindsley %T BCOR and BCORL1 mutations disrupt PRC1.1 repressive function in leukemia by unlinking the RING-PCGF1 enzymatic core from target genes %D 2021 %R 10.1101/2021.03.08.433705 %J bioRxiv %P 2021.03.08.433705 %X BCOR and its paralog BCORL1 encode subunits of the Polycomb repressive complex 1.1 (PRC1.1) and are recurrently mutated in myeloid malignancies. We show that leukemia-associated BCOR/BCORL1 mutations unlink the PRC1.1 RING-PCGF enzymatic core from the KDM2B-containing chromatin targeting auxiliary subcomplex, either by causing complete protein loss or expression of a C-terminally truncated protein lacking the PCGF Ub-like fold discriminator (PUFD) domain. By uncoupling PRC1.1 repressive function from target genes, BCOR/BCORL1 mutations activate aberrant cell signaling programs that confer acquired resistance to treatment. This study provides a mechanistic basis for Polycomb repressive dysfunction as a key oncogenic driver in myeloid malignancies and identifies a potential strategy for targeted therapy in BCOR-mutated cancer.Competing Interest StatementThe authors have declared no competing interest. %U https://www.biorxiv.org/content/biorxiv/early/2021/03/08/2021.03.08.433705.full.pdf