TY - JOUR T1 - <em>BCOR</em> and <em>BCORL1</em> mutations disrupt PRC1.1 repressive function in leukemia by unlinking the RING-PCGF1 enzymatic core from target genes JF - bioRxiv DO - 10.1101/2021.03.08.433705 SP - 2021.03.08.433705 AU - Eva J. Schaefer AU - Helen C. Wang AU - Clifford A. Meyer AU - Paloma Cejas AU - Micah D. Gearhart AU - Emmalee R. Adelman AU - Iman Fares AU - Annie Apffel AU - Klothilda Lim AU - Yingtian Xie AU - Christopher J. Gibson AU - Monica Schenone AU - H. Moses Murdock AU - Eunice S. Wang AU - Lukasz P. Gondek AU - Martin P. Carroll AU - Rahul S. Vedula AU - Eric S. Winer AU - Jacqueline S. Garcia AU - Richard M. Stone AU - Marlise R. Luskin AU - Steven A. Carr AU - Henry W. Long AU - Vivian J. Bardwell AU - Maria E. Figueroa AU - R. Coleman Lindsley Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/03/08/2021.03.08.433705.abstract N2 - 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. ER -