PRMT5 inhibition modulates E2F1 methylation and gene-regulatory networks leading to therapeutic efficacy in JAK2(V617F)-mutant MPN Journal Article


Authors: Pastore, F.; Bhagwat, N.; Pastore, A.; Radzisheuskaya, A.; Karzai, A.; Krishnan, A.; Li, B.; Bowman, R. L.; Xiao, W.; Viny, A. D.; Zouak, A.; Park, Y. C.; Cordner, K. B.; Braunstein, S.; Maag, J. L.; Grego, A.; Mehta, J.; Wang, M.; Lin, H.; Durham, B. H.; Koche, R. P.; Rampal, R. K.; Helin, K.; Scherle, P.; Vaddi, K.; Levine, R. L.
Article Title: PRMT5 inhibition modulates E2F1 methylation and gene-regulatory networks leading to therapeutic efficacy in JAK2(V617F)-mutant MPN
Abstract: We investigated the role of PRMT5 in myeloproliferative neoplasm (MPN) pathogenesis and aimed to elucidate key PRMTS targets contributing to MPN maintenance. PRMTS 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 JAK2(V)(617)(F+) 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 PRMTS 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 PRMTS 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 JAK2(V)(617)(F+) MPN. Pharmacologic inhibition of PRMT5 alters the methylation status of E2F1 and shows efficacy in JAK2(V)(617)(F)/MPLW515L MPN models and primary samples. PRMT5 represents a potential novel therapeutic target for MPN, which is now being clinically evaluated.
Keywords: mutation; neoplasm; model; murine; cells; jak2 inhibitor; myeloproliferative; hematopoietic stem; arginine methyltransferase; ruxolitinib; available therapy; stat pathway activation
Journal Title: Cancer Discovery
Volume: 10
Issue: 11
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2020-11-01
Start Page: 1742
End Page: 1757
Language: English
ACCESSION: WOS:000583736200027
DOI: 10.1158/2159-8290.Cd-20-0026
PROVIDER: wos
PMCID: PMC7642059
PUBMED: 32669286
Notes: Article -- Source: Wos
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MSK Authors
  1. Raajit Kumar Rampal
    204 Rampal
  2. Ross Levine
    624 Levine
  3. Robert L Bowman
    37 Bowman
  4. Richard Patrick Koche
    97 Koche
  5. Aaron David Viny
    46 Viny
  6. Benjamin Heath Durham
    86 Durham
  7. Friederike   Pastore
    12 Pastore
  8. Alessandro   Pastore
    45 Pastore
  9. Wenbin Xiao
    51 Xiao
  10. Jesper Lars Viktor Maag
    10 Maaaag
  11. Bing Li
    5 Li
  12. Kristian Helin
    18 Helin
  13. Anouar Zouak
    3 Zouak
  14. Abdul Karzai
    4 Karzai
  15. Young Park
    7 Park