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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

Eva J. Schaefer, Helen C. Wang, Clifford A. Meyer, Paloma Cejas, Micah D. Gearhart, Emmalee R. Adelman, Iman Fares, Annie Apffel, Klothilda Lim, Yingtian Xie, Christopher J. Gibson, Monica Schenone, H. Moses Murdock, Eunice S. Wang, Lukasz P. Gondek, View ORCID ProfileMartin P. Carroll, Rahul S. Vedula, Eric S. Winer, Jacqueline S. Garcia, Richard M. Stone, Marlise R. Luskin, Steven A. Carr, View ORCID ProfileHenry W. Long, Vivian J. Bardwell, Maria E. Figueroa, R. Coleman Lindsley
doi: https://doi.org/10.1101/2021.03.08.433705
Eva J. Schaefer
1Department of Medical Oncology, Division of Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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Helen C. Wang
1Department of Medical Oncology, Division of Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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Clifford A. Meyer
2Department of Data Science, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA
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Paloma Cejas
3Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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Micah D. Gearhart
4Developmental Biology Center, Masonic Cancer Center, and Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA
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Emmalee R. Adelman
5Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA
6Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL 33136, USA
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Iman Fares
1Department of Medical Oncology, Division of Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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Annie Apffel
7Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
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Klothilda Lim
3Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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Yingtian Xie
3Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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Christopher J. Gibson
1Department of Medical Oncology, Division of Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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Monica Schenone
7Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
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H. Moses Murdock
1Department of Medical Oncology, Division of Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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Eunice S. Wang
8Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
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Lukasz P. Gondek
9Division of Molecular Pathology, Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA
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Martin P. Carroll
10Department of Medicine, Perelman Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
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  • ORCID record for Martin P. Carroll
Rahul S. Vedula
1Department of Medical Oncology, Division of Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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Eric S. Winer
1Department of Medical Oncology, Division of Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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Jacqueline S. Garcia
1Department of Medical Oncology, Division of Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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Richard M. Stone
1Department of Medical Oncology, Division of Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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Marlise R. Luskin
1Department of Medical Oncology, Division of Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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Steven A. Carr
7Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
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Henry W. Long
3Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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  • ORCID record for Henry W. Long
Vivian J. Bardwell
4Developmental Biology Center, Masonic Cancer Center, and Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA
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Maria E. Figueroa
5Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA
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R. Coleman Lindsley
1Department of Medical Oncology, Division of Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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  • For correspondence: coleman_lindsley@dfci.harvard.edu
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Summary

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 Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 08, 2021.
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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
Eva J. Schaefer, Helen C. Wang, Clifford A. Meyer, Paloma Cejas, Micah D. Gearhart, Emmalee R. Adelman, Iman Fares, Annie Apffel, Klothilda Lim, Yingtian Xie, Christopher J. Gibson, Monica Schenone, H. Moses Murdock, Eunice S. Wang, Lukasz P. Gondek, Martin P. Carroll, Rahul S. Vedula, Eric S. Winer, Jacqueline S. Garcia, Richard M. Stone, Marlise R. Luskin, Steven A. Carr, Henry W. Long, Vivian J. Bardwell, Maria E. Figueroa, R. Coleman Lindsley
bioRxiv 2021.03.08.433705; doi: https://doi.org/10.1101/2021.03.08.433705
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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
Eva J. Schaefer, Helen C. Wang, Clifford A. Meyer, Paloma Cejas, Micah D. Gearhart, Emmalee R. Adelman, Iman Fares, Annie Apffel, Klothilda Lim, Yingtian Xie, Christopher J. Gibson, Monica Schenone, H. Moses Murdock, Eunice S. Wang, Lukasz P. Gondek, Martin P. Carroll, Rahul S. Vedula, Eric S. Winer, Jacqueline S. Garcia, Richard M. Stone, Marlise R. Luskin, Steven A. Carr, Henry W. Long, Vivian J. Bardwell, Maria E. Figueroa, R. Coleman Lindsley
bioRxiv 2021.03.08.433705; doi: https://doi.org/10.1101/2021.03.08.433705

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