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BCOR and BCORL1 mutations disrupt PRC1.1 repressive function in leukemia by unlinking the RING-PCGF1 enzymatic core from target genes

Schaefer, E. J.; Wang, W. C.; Meyer, C. A.; Cejas, P.; Gearhart, M. D.; Adelman, E. R.; Fares, I.; Apffel, A.; Lim, K.; Xie, Y.; Gibson, C. J.; Schenone, M.; Murdock, H. M.; Wang, E. S.; Gondek, L. P.; Carroll, M. P.; Vedula, R. S.; Winer, E. S.; Garcia, J. S.; Stone, R. M.; Luskin, M. R.; Carr, S. A.; Long, H. W.; Bardwell, V. J.; Figueroa, M. E.; Lindsley, R. C.

2021-03-08 cancer biology
10.1101/2021.03.08.433705 bioRxiv
Show 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.

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