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.