2. Academic Validation
  3. PRMT5 Inhibition Modulates E2F1 Methylation and Gene-Regulatory Networks Leading to Therapeutic Efficacy in JAK2V617F-Mutant MPN

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

  • Cancer Discov. 2020 Nov;10(11):1742-1757. doi: 10.1158/2159-8290.CD-20-0026.
Friederike Pastore 1 2,  Neha Bhagwat 3,  Alessandro Pastore 1,  Aliaksandra Radzisheuskaya 2 4,  Abdul Karzai 1 2,  Aishwarya Krishnan 1 2,  Bing Li 1 2,  Robert L Bowman 1 2,  Wenbin Xiao 1 2 5,  Aaron D Viny 1 2,  Anouar Zouak 1 2,  Young C Park 1 2,  Keith B Cordner 1 2,  Stephanie Braunstein 1 2,  Jesper L Maag 2,  Alexander Grego 3,  Jaanvi Mehta 3,  Min Wang 3,  Hong Lin 3,  Benjamin H Durham 1,  Richard P Koche 2,  Raajit K Rampal 1 6,  Kristian Helin 2 4 7 8,  Peggy Scherle 3,  Kris Vaddi 3,  Ross L Levine 9 2 6 10
Affiliations

Affiliations

  • 1 Molecular Cancer Medicine Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 2 Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 3 Prelude Therapeutics Inc., Wilmington, Delaware.
  • 4 Cell Biology Program, Memorial Sloan Kettering CancerCenter, New York, New York.
  • 5 Hematopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 6 Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 7 Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
  • 8 The Novo Nordisk Foundation of Stem Cell Research (Danstem), University of Copenhagen, Copenhagen, Denmark.
  • 9 Molecular Cancer Medicine Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. [email protected].
  • 10 Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York.
PMID: 32669286 DOI: 10.1158/2159-8290.CD-20-0026
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.

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