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)

Research output: Contribution to journal › Article › peer-review

25 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

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Publisher Copyright:
©2021 American Association for Cancer Research.

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10.1158/2643-3230.BCD-21-0115

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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 = "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)",

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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

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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SN - 2643-3230

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JO - Blood cancer discovery

JF - Blood cancer discovery

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ER -

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

Abstract

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