PRMT5 Inhibition Modulates E2F1 Methylation and Gene-Regulatory Networks Leading to Therapeutic Efficacy in JAK2V617F-Mutant MPN
| Autor: | Hong Lin, Richard Koche, Stephanie Braunstein, Anouar Zouak, Bing Li, Aliaksandra Radzisheuskaya, Peggy Scherle, Min Wang, Aishwarya Krishnan, Kris Vaddi, Young C. Park, Raajit K. Rampal, Abdul Karzai, Neha Bhagwat, Benjamin H. Durham, Aaron D. Viny, Friederike Pastore, Robert L. Bowman, Alexander Grego, Wenbin Xiao, Ross L. Levine, Keith B. Cordner, Jesper L.V. Maag, Jaanvi Mehta, Kristian Helin, Alessandro Pastore |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
business.industry Cell growth food and beverages Methylation medicine.disease 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Polycythemia vera Oncology In vivo 030220 oncology & carcinogenesis medicine Cancer research E2F1 business Myelofibrosis Myeloproliferative neoplasm Ex vivo |
| Zdroj: | Cancer Discovery. 10:1742-1757 |
| ISSN: | 2159-8290 2159-8274 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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