BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes

Eva J. Schaefer; Helen C. Wang; Hannah Q. Karp; 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

doi:10.1158/2643-3230.BCD-21-0115

BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes

Eva J. Schaefer, Helen C. Wang, Hannah Q. Karp, 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. GarciaRichard M. Stone, Marlise R. Luskin, Steven A. Carr, Henry W. Long, Vivian J Bardwell, Maria E. Figueroa, R. Coleman Lindsley

Genetics, Cell Biology and Development (TMED)

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15 Scopus citations

Abstract

Polycomb repressive epigenetic complexes are recurrently dysregulated in cancer. Unlike polycomb repressive complex 2 (PRC2), the role of PRC1 in oncogenesis and therapy resistance is not well-defined. Here, we demonstrate that highly recurrent mutations of the PRC1 subunits BCOR and BCORL1 in leukemia disrupt assembly of a noncanonical PRC1.1 complex, thereby selectively unlinking the RING-PCGF enzymatic core from the chromatin-targeting auxiliary subcomplex. As a result, BCOR-mutated PRC1.1 is localized to chromatin but lacks repressive activity, leading to epigenetic reprogramming and transcriptional activation at target loci. We define a set of functional targets that drive aberrant oncogenic signaling programs in PRC1.1-mutated cells and primary patient samples. Activation of these PRC1.1 targets in BCOR-mutated cells confers acquired resistance to treatment while sensitizing to targeted kinase inhibition. Our study thus reveals a novel epigenetic mechanism that explains PRC1.1 tumor-suppressive activity and identifies a therapeutic strategy in PRC1.1-mutated cancer.

Original language	English (US)
Pages (from-to)	116-135
Number of pages	20
Journal	Blood cancer discovery
Volume	3
Issue number	2
DOIs	https://doi.org/10.1158/2643-3230.BCD-21-0115
State	Published - Mar 1 2022

Bibliographical note

Funding Information:
E.J. Schaefer reports grants from the German Research Foundation (DFG) and Research School for Translational Medicine Goettingen (TRANSMED) during the conduct of the study. I. Fares reports grants from Canadian Institutes of Health Research (CIHR)-Banting Postdoctoral Fellowship during the conduct of the study. E.S. Winer reports other support from Pfizer, Jazz Pharmaceuticals, Curis, and Takeda outside the submitted work. J.S. Garcia reports nonfinancial support and other support from AbbVie; nonfinancial support from Genentech; personal fees from Astellas; and other support from Prelude, AstraZeneca, and Pfizer outside the submitted work. R.M. Stone reports personal fees from AbbVie, AbbVie/ Genentech, Actinium, Amgen, Aprea, Astellas, Biolinerx, BerGenBio, Bristol Myers Squibb, Boston Pharmaceuticals, CTI Pharma, Daiichi Sankyo, Elevate Bio, Foghorn, Gemoab, GlaxoSmithKline, Innate, Janssen, Jazz, Macrogenics, OncoNova, Syros, Takeda, and Trovagene; personal fees and other support from Arog and Novartis; and other support from Celgene and Syntrix/ACI outside the submitted work. S.A. Carr is a scientific advisory board member for Kymera, PTMBio, and Seer. V.J. Bardwell reports grants from the NIH during the conduct of the study. M.E. Figueroa reports grants from the Leukemia & Lymphoma Society during the conduct of the study. R.C. Lindsley reports grants from the Edward P. Evans Foundation and NIH during the conduct of the study, as well as personal fees from Takeda Pharmaceuticals and Bluebird Bio, and other support from Jazz Pharmaceuticals outside the submitted work. No disclosures were reported by the other authors.

Funding Information:
This work was supported by the NIH [K08CA204734 (R.C. Lindsley) and R01HD084459 (V.J. Bardwell)], the Edward P. Evans Foundation (R.C. Lindsley), the German Research Foundation [DFG-SCHA2121/1-1 (E.J. Schaefer)], and the Research School for Translational Medicine Goettingen (E.J. Schaefer). This work was supported by the Dana-Farber Cancer Institute Center for Functional Cancer Epigenetics, the Ted and Eileen Pasquarello Tissue Bank in Hematologic Malignancies, and the Dana-Farber Cancer Institute Hematologic Malignancies Data Repository.

Publisher Copyright:
©2021 American Association for Cancer Research.

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Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

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Schaefer, E. J., Wang, H. C., Karp, H. Q., 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., ... Lindsley, R. C. (2022). BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes. Blood cancer discovery, 3(2), 116-135. https://doi.org/10.1158/2643-3230.BCD-21-0115

Schaefer, EJ, Wang, HC, Karp, HQ, Meyer, CA, Cejas, P, Gearhart, MD, Adelman, ER, Fares, I, Apffel, A, Lim, K, Xie, Y, Gibson, CJ, Schenone, M, Murdock, HM, Wang, ES, Gondek, LP, Carroll, MP, Vedula, RS, Winer, ES, Garcia, JS, Stone, RM, Luskin, MR, Carr, SA, Long, HW, Bardwell, VJ, Figueroa, ME & Lindsley, RC 2022, 'BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes', Blood cancer discovery, vol. 3, no. 2, pp. 116-135. https://doi.org/10.1158/2643-3230.BCD-21-0115

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title = "BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes",

abstract = "Polycomb repressive epigenetic complexes are recurrently dysregulated in cancer. Unlike polycomb repressive complex 2 (PRC2), the role of PRC1 in oncogenesis and therapy resistance is not well-defined. Here, we demonstrate that highly recurrent mutations of the PRC1 subunits BCOR and BCORL1 in leukemia disrupt assembly of a noncanonical PRC1.1 complex, thereby selectively unlinking the RING-PCGF enzymatic core from the chromatin-targeting auxiliary subcomplex. As a result, BCOR-mutated PRC1.1 is localized to chromatin but lacks repressive activity, leading to epigenetic reprogramming and transcriptional activation at target loci. We define a set of functional targets that drive aberrant oncogenic signaling programs in PRC1.1-mutated cells and primary patient samples. Activation of these PRC1.1 targets in BCOR-mutated cells confers acquired resistance to treatment while sensitizing to targeted kinase inhibition. Our study thus reveals a novel epigenetic mechanism that explains PRC1.1 tumor-suppressive activity and identifies a therapeutic strategy in PRC1.1-mutated cancer.",

author = "Schaefer, {Eva J.} and Wang, {Helen C.} and Karp, {Hannah Q.} and Meyer, {Clifford A.} and Paloma Cejas and Gearhart, {Micah D.} and Adelman, {Emmalee R.} and Iman Fares and Annie Apffel and Klothilda Lim and Yingtian Xie and Gibson, {Christopher J.} and Monica Schenone and Murdock, {H. Moses} and Wang, {Eunice S.} and Gondek, {Lukasz P.} and Carroll, {Martin P.} and Vedula, {Rahul S.} and Winer, {Eric S.} and Garcia, {Jacqueline S.} and Stone, {Richard M.} and Luskin, {Marlise R.} and Carr, {Steven A.} and Long, {Henry W.} and Bardwell, {Vivian J} and Figueroa, {Maria E.} and Lindsley, {R. Coleman}",

note = "Funding Information: E.J. Schaefer reports grants from the German Research Foundation (DFG) and Research School for Translational Medicine Goettingen (TRANSMED) during the conduct of the study. I. Fares reports grants from Canadian Institutes of Health Research (CIHR)-Banting Postdoctoral Fellowship during the conduct of the study. E.S. Winer reports other support from Pfizer, Jazz Pharmaceuticals, Curis, and Takeda outside the submitted work. J.S. Garcia reports nonfinancial support and other support from AbbVie; nonfinancial support from Genentech; personal fees from Astellas; and other support from Prelude, AstraZeneca, and Pfizer outside the submitted work. R.M. Stone reports personal fees from AbbVie, AbbVie/ Genentech, Actinium, Amgen, Aprea, Astellas, Biolinerx, BerGenBio, Bristol Myers Squibb, Boston Pharmaceuticals, CTI Pharma, Daiichi Sankyo, Elevate Bio, Foghorn, Gemoab, GlaxoSmithKline, Innate, Janssen, Jazz, Macrogenics, OncoNova, Syros, Takeda, and Trovagene; personal fees and other support from Arog and Novartis; and other support from Celgene and Syntrix/ACI outside the submitted work. S.A. Carr is a scientific advisory board member for Kymera, PTMBio, and Seer. V.J. Bardwell reports grants from the NIH during the conduct of the study. M.E. Figueroa reports grants from the Leukemia & Lymphoma Society during the conduct of the study. R.C. Lindsley reports grants from the Edward P. Evans Foundation and NIH during the conduct of the study, as well as personal fees from Takeda Pharmaceuticals and Bluebird Bio, and other support from Jazz Pharmaceuticals outside the submitted work. No disclosures were reported by the other authors. Funding Information: This work was supported by the NIH [K08CA204734 (R.C. Lindsley) and R01HD084459 (V.J. Bardwell)], the Edward P. Evans Foundation (R.C. Lindsley), the German Research Foundation [DFG-SCHA2121/1-1 (E.J. Schaefer)], and the Research School for Translational Medicine Goettingen (E.J. Schaefer). This work was supported by the Dana-Farber Cancer Institute Center for Functional Cancer Epigenetics, the Ted and Eileen Pasquarello Tissue Bank in Hematologic Malignancies, and the Dana-Farber Cancer Institute Hematologic Malignancies Data Repository. Publisher Copyright: {\textcopyright}2021 American Association for Cancer Research.",

year = "2022",

month = mar,

day = "1",

doi = "10.1158/2643-3230.BCD-21-0115",

language = "English (US)",

volume = "3",

pages = "116--135",

journal = "Blood cancer discovery",

issn = "2643-3230",

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T1 - BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes

AU - Schaefer, Eva J.

AU - Wang, Helen C.

AU - Karp, Hannah Q.

AU - Meyer, Clifford A.

AU - Cejas, Paloma

AU - Gearhart, Micah D.

AU - Adelman, Emmalee R.

AU - Fares, Iman

AU - Apffel, Annie

AU - Lim, Klothilda

AU - Xie, Yingtian

AU - Gibson, Christopher J.

AU - Schenone, Monica

AU - Murdock, H. Moses

AU - Wang, Eunice S.

AU - Gondek, Lukasz P.

AU - Carroll, Martin P.

AU - Vedula, Rahul S.

AU - Winer, Eric S.

AU - Garcia, Jacqueline S.

AU - Stone, Richard M.

AU - Luskin, Marlise R.

AU - Carr, Steven A.

AU - Long, Henry W.

AU - Bardwell, Vivian J

AU - Figueroa, Maria E.

AU - Lindsley, R. Coleman

N1 - Funding Information: E.J. Schaefer reports grants from the German Research Foundation (DFG) and Research School for Translational Medicine Goettingen (TRANSMED) during the conduct of the study. I. Fares reports grants from Canadian Institutes of Health Research (CIHR)-Banting Postdoctoral Fellowship during the conduct of the study. E.S. Winer reports other support from Pfizer, Jazz Pharmaceuticals, Curis, and Takeda outside the submitted work. J.S. Garcia reports nonfinancial support and other support from AbbVie; nonfinancial support from Genentech; personal fees from Astellas; and other support from Prelude, AstraZeneca, and Pfizer outside the submitted work. R.M. Stone reports personal fees from AbbVie, AbbVie/ Genentech, Actinium, Amgen, Aprea, Astellas, Biolinerx, BerGenBio, Bristol Myers Squibb, Boston Pharmaceuticals, CTI Pharma, Daiichi Sankyo, Elevate Bio, Foghorn, Gemoab, GlaxoSmithKline, Innate, Janssen, Jazz, Macrogenics, OncoNova, Syros, Takeda, and Trovagene; personal fees and other support from Arog and Novartis; and other support from Celgene and Syntrix/ACI outside the submitted work. S.A. Carr is a scientific advisory board member for Kymera, PTMBio, and Seer. V.J. Bardwell reports grants from the NIH during the conduct of the study. M.E. Figueroa reports grants from the Leukemia & Lymphoma Society during the conduct of the study. R.C. Lindsley reports grants from the Edward P. Evans Foundation and NIH during the conduct of the study, as well as personal fees from Takeda Pharmaceuticals and Bluebird Bio, and other support from Jazz Pharmaceuticals outside the submitted work. No disclosures were reported by the other authors. Funding Information: This work was supported by the NIH [K08CA204734 (R.C. Lindsley) and R01HD084459 (V.J. Bardwell)], the Edward P. Evans Foundation (R.C. Lindsley), the German Research Foundation [DFG-SCHA2121/1-1 (E.J. Schaefer)], and the Research School for Translational Medicine Goettingen (E.J. Schaefer). This work was supported by the Dana-Farber Cancer Institute Center for Functional Cancer Epigenetics, the Ted and Eileen Pasquarello Tissue Bank in Hematologic Malignancies, and the Dana-Farber Cancer Institute Hematologic Malignancies Data Repository. Publisher Copyright: ©2021 American Association for Cancer Research.

PY - 2022/3/1

Y1 - 2022/3/1

N2 - Polycomb repressive epigenetic complexes are recurrently dysregulated in cancer. Unlike polycomb repressive complex 2 (PRC2), the role of PRC1 in oncogenesis and therapy resistance is not well-defined. Here, we demonstrate that highly recurrent mutations of the PRC1 subunits BCOR and BCORL1 in leukemia disrupt assembly of a noncanonical PRC1.1 complex, thereby selectively unlinking the RING-PCGF enzymatic core from the chromatin-targeting auxiliary subcomplex. As a result, BCOR-mutated PRC1.1 is localized to chromatin but lacks repressive activity, leading to epigenetic reprogramming and transcriptional activation at target loci. We define a set of functional targets that drive aberrant oncogenic signaling programs in PRC1.1-mutated cells and primary patient samples. Activation of these PRC1.1 targets in BCOR-mutated cells confers acquired resistance to treatment while sensitizing to targeted kinase inhibition. Our study thus reveals a novel epigenetic mechanism that explains PRC1.1 tumor-suppressive activity and identifies a therapeutic strategy in PRC1.1-mutated cancer.

AB - Polycomb repressive epigenetic complexes are recurrently dysregulated in cancer. Unlike polycomb repressive complex 2 (PRC2), the role of PRC1 in oncogenesis and therapy resistance is not well-defined. Here, we demonstrate that highly recurrent mutations of the PRC1 subunits BCOR and BCORL1 in leukemia disrupt assembly of a noncanonical PRC1.1 complex, thereby selectively unlinking the RING-PCGF enzymatic core from the chromatin-targeting auxiliary subcomplex. As a result, BCOR-mutated PRC1.1 is localized to chromatin but lacks repressive activity, leading to epigenetic reprogramming and transcriptional activation at target loci. We define a set of functional targets that drive aberrant oncogenic signaling programs in PRC1.1-mutated cells and primary patient samples. Activation of these PRC1.1 targets in BCOR-mutated cells confers acquired resistance to treatment while sensitizing to targeted kinase inhibition. Our study thus reveals a novel epigenetic mechanism that explains PRC1.1 tumor-suppressive activity and identifies a therapeutic strategy in PRC1.1-mutated cancer.

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BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes

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