%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