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PRMT5 Inhibition Modulates E2F1 Methylation and Gene-Regulatory Networks Leading to Therapeutic Efficacy in JAK2V617F-Mutant MPN

Friederike Pastore, Neha Bhagwat, Alessandro Pastore, Aliaksandra Radzisheuskaya, Abdul Karzai, Aishwarya Krishnan, Bing Li, Robert L. Bowman, Wenbin Xiao, Aaron D. Viny, Anouar Zouak, Young C. Park, Keith B. Cordner, Stephanie Braunstein, Jesper L. Maag, Alexander Grego, Jaanvi Mehta, Min Wang, Hong Lin, Benjamin H. Durham, Richard P. Koche, Raajit K. Rampal, Kristian Helin, Peggy Scherle, Kris Vaddi and Ross L. Levine
Friederike Pastore
1Molecular Cancer Medicine Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
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Neha Bhagwat
3Prelude Therapeutics Inc., Wilmington, Delaware.
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Alessandro Pastore
1Molecular Cancer Medicine Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Aliaksandra Radzisheuskaya
2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
4Cell Biology Program, Memorial Sloan Kettering CancerCenter, New York, New York.
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Abdul Karzai
1Molecular Cancer Medicine Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
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Aishwarya Krishnan
1Molecular Cancer Medicine Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
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Bing Li
1Molecular Cancer Medicine Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
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Robert L. Bowman
1Molecular Cancer Medicine Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
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Wenbin Xiao
1Molecular Cancer Medicine Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
5Hematopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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  • ORCID record for Wenbin Xiao
Aaron D. Viny
1Molecular Cancer Medicine Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
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Anouar Zouak
1Molecular Cancer Medicine Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
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Young C. Park
1Molecular Cancer Medicine Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
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Keith B. Cordner
1Molecular Cancer Medicine Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
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Stephanie Braunstein
1Molecular Cancer Medicine Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
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Jesper L. Maag
2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
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  • ORCID record for Jesper L. Maag
Alexander Grego
3Prelude Therapeutics Inc., Wilmington, Delaware.
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Jaanvi Mehta
3Prelude Therapeutics Inc., Wilmington, Delaware.
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Min Wang
3Prelude Therapeutics Inc., Wilmington, Delaware.
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Hong Lin
3Prelude Therapeutics Inc., Wilmington, Delaware.
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Benjamin H. Durham
1Molecular Cancer Medicine Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Richard P. Koche
2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
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Raajit K. Rampal
1Molecular Cancer Medicine Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
6Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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Kristian Helin
2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
4Cell Biology Program, Memorial Sloan Kettering CancerCenter, New York, New York.
7Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
8The Novo Nordisk Foundation of Stem Cell Research (Danstem), University of Copenhagen, Copenhagen, Denmark.
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Peggy Scherle
3Prelude Therapeutics Inc., Wilmington, Delaware.
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Kris Vaddi
3Prelude Therapeutics Inc., Wilmington, Delaware.
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Ross L. Levine
1Molecular Cancer Medicine Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
6Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
9Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York.
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  • For correspondence: leviner@mskcc.org
DOI: 10.1158/2159-8290.CD-20-0026 Published November 2020
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Abstract

We investigated the role of PRMT5 in myeloproliferative neoplasm (MPN) pathogenesis and aimed to elucidate key PRMT5 targets contributing to MPN maintenance. PRMT5 is overexpressed in primary MPN cells, and PRMT5 inhibition potently reduced MPN cell proliferation ex vivo. PRMT5 inhibition was efficacious at reversing elevated hematocrit, leukocytosis, and splenomegaly in a model of JAK2V617F+ polycythemia vera and leukocyte and platelet counts, hepatosplenomegaly, and fibrosis in the MPLW515L model of myelofibrosis. Dual targeting of JAK and PRMT5 was superior to JAK or PRMT5 inhibitor monotherapy, further decreasing elevated counts and extramedullary hematopoiesis in vivo. PRMT5 inhibition reduced expression of E2F targets and altered the methylation status of E2F1 leading to attenuated DNA damage repair, cell-cycle arrest, and increased apoptosis. Our data link PRMT5 to E2F1 regulatory function and MPN cell survival and provide a strong mechanistic rationale for clinical trials of PRMT5 inhibitors in MPN.

Significance: Expression of PRMT5 and E2F targets is increased in JAK2V617F+ MPN. Pharmacologic inhibition of PRMT5 alters the methylation status of E2F1 and shows efficacy in JAK2V617F/MPLW515L MPN models and primary samples. PRMT5 represents a potential novel therapeutic target for MPN, which is now being clinically evaluated.

This article is highlighted in the In This Issue feature, p. 1611

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Cancer Discov 2020;10:1742–57

  • Received January 8, 2020.
  • Revision received May 26, 2020.
  • Accepted July 10, 2020.
  • Published first July 15, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Discovery: 10 (11)
November 2020
Volume 10, Issue 11
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PRMT5 Inhibition Modulates E2F1 Methylation and Gene-Regulatory Networks Leading to Therapeutic Efficacy in JAK2V617F-Mutant MPN
Friederike Pastore, Neha Bhagwat, Alessandro Pastore, Aliaksandra Radzisheuskaya, Abdul Karzai, Aishwarya Krishnan, Bing Li, Robert L. Bowman, Wenbin Xiao, Aaron D. Viny, Anouar Zouak, Young C. Park, Keith B. Cordner, Stephanie Braunstein, Jesper L. Maag, Alexander Grego, Jaanvi Mehta, Min Wang, Hong Lin, Benjamin H. Durham, Richard P. Koche, Raajit K. Rampal, Kristian Helin, Peggy Scherle, Kris Vaddi and Ross L. Levine
Cancer Discov November 1 2020 (10) (11) 1742-1757; DOI: 10.1158/2159-8290.CD-20-0026

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PRMT5 Inhibition Modulates E2F1 Methylation and Gene-Regulatory Networks Leading to Therapeutic Efficacy in JAK2V617F-Mutant MPN
Friederike Pastore, Neha Bhagwat, Alessandro Pastore, Aliaksandra Radzisheuskaya, Abdul Karzai, Aishwarya Krishnan, Bing Li, Robert L. Bowman, Wenbin Xiao, Aaron D. Viny, Anouar Zouak, Young C. Park, Keith B. Cordner, Stephanie Braunstein, Jesper L. Maag, Alexander Grego, Jaanvi Mehta, Min Wang, Hong Lin, Benjamin H. Durham, Richard P. Koche, Raajit K. Rampal, Kristian Helin, Peggy Scherle, Kris Vaddi and Ross L. Levine
Cancer Discov November 1 2020 (10) (11) 1742-1757; DOI: 10.1158/2159-8290.CD-20-0026
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