RT Journal Article SR Electronic T1 BCOR and BCORL1 mutations disrupt PRC1.1 repressive function in leukemia by unlinking the RING-PCGF1 enzymatic core from target genes JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.03.08.433705 DO 10.1101/2021.03.08.433705 A1 Eva J. Schaefer A1 Helen C. Wang A1 Clifford A. Meyer A1 Paloma Cejas A1 Micah D. Gearhart A1 Emmalee R. Adelman A1 Iman Fares A1 Annie Apffel A1 Klothilda Lim A1 Yingtian Xie A1 Christopher J. Gibson A1 Monica Schenone A1 H. Moses Murdock A1 Eunice S. Wang A1 Lukasz P. Gondek A1 Martin P. Carroll A1 Rahul S. Vedula A1 Eric S. Winer A1 Jacqueline S. Garcia A1 Richard M. Stone A1 Marlise R. Luskin A1 Steven A. Carr A1 Henry W. Long A1 Vivian J. Bardwell A1 Maria E. Figueroa A1 R. Coleman Lindsley YR 2021 UL http://biorxiv.org/content/early/2021/03/08/2021.03.08.433705.abstract AB 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.