@article {Schaefer2021.03.08.433705, author = {Eva J. Schaefer and Helen C. Wang and Clifford A. Meyer and Paloma Cejas and Micah D. Gearhart and Emmalee R. Adelman and Iman Fares and Annie Apffel and Klothilda Lim and Yingtian Xie and Christopher J. Gibson and Monica Schenone and H. Moses Murdock and Eunice S. Wang and Lukasz P. Gondek and Martin P. Carroll and Rahul S. Vedula and Eric S. Winer and Jacqueline S. Garcia and Richard M. Stone and Marlise R. Luskin and Steven A. Carr and Henry W. Long and Vivian J. Bardwell and Maria E. Figueroa and R. Coleman Lindsley}, title = {BCOR and BCORL1 mutations disrupt PRC1.1 repressive function in leukemia by unlinking the RING-PCGF1 enzymatic core from target genes}, elocation-id = {2021.03.08.433705}, year = {2021}, doi = {10.1101/2021.03.08.433705}, publisher = {Cold Spring Harbor Laboratory}, abstract = {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.}, URL = {https://www.biorxiv.org/content/early/2021/03/08/2021.03.08.433705}, eprint = {https://www.biorxiv.org/content/early/2021/03/08/2021.03.08.433705.full.pdf}, journal = {bioRxiv} }