Reference Detail

Ref Type

Journal Article

PMID

(32669286)

Authors

Pastore F, Bhagwat N, Pastore A, Radzisheuskaya A, Karzai A, Krishnan A, Li B, Bowman RL, Xiao W, Viny AD, Zouak A, Park YC, Cordner KB, Braunstein S, Maag JL, Grego A, Mehta J, Wang M, Lin H, Durham BH, Koche RP, Rampal RK, Helin K, Scherle P, Vaddi K, Levine RL

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	10	11	2020 Nov	1742-1757	Cancer Discov

URL

Abstract Text

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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
C220	C220	4	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
C220			PRMT5 Inhibitor 17	C220 is a small molecule inhibitor that selectively targets PRMT5, which may lead to decreased cell proliferation and reduced secretion of cytokines (PMID: 32669286).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
JAK2 V617F	polycythemia vera	predicted - sensitive	C220	Preclinical	Actionable	In a preclinical study, C220 treatment in a transgenic mouse model of polycythemia vera expressing JAK2 V617F resulted in decreased white blood cell counts, reduced spleen size with decreased extramedullary hematopoeisis, and decreased myeloproliferation, and altered the proportion of erythroid progenitors and erythroblasts (PMID: 32669286).	32669286
JAK2 V617F	myeloproliferative neoplasm	predicted - sensitive	C220	Preclinical - Cell line xenograft	Actionable	In a preclinical study, C220 treatment inhibited cell proliferation of myeloproliferative neoplasm cell lines, including a Jakafi (ruxolitinib)-persistent cell line, expressing JAK2 V617F in culture, and inhibited tumor growth, with a 71% tumor reduction, in a cell line xenograft model (PMID: 32669286).	32669286
JAK2 V617F	hematologic cancer	predicted - sensitive	C220	Preclinical - Cell culture	Actionable	In a preclinical study, C220 treatment inhibited proliferation of transformed cells expressing JAK2 V617F in culture (PMID: 32669286).	32669286
JAK2 V617F	myelofibrosis	predicted - sensitive	C220	Preclinical - Patient cell culture	Actionable	In a preclinical study, patient-derived primary myelofibrosis cells harboring JAK2 V617F and positive for CD34 were sensitive to C220 treatment in culture (PMID: 32669286).	32669286
JAK2 V617F	polycythemia vera	predicted - sensitive	C220 + Ruxolitinib	Preclinical	Actionable	In a preclinical study, combination of C220 and Jakafi (ruxolitinib) treatment in a transgenic mouse model of polycythemia vera expressing JAK2 V617F resulted in reduced white blood cell count, decreased spleen and liver size, reduced bone marrow hypercellularity, reduced erythroid, megakaryocyte and myeloid progenitors, and inhibition of inflammatory cytokines to a greater degree than single agent alone. (PMID: 32669286).	32669286
JAK2 V617F	myeloproliferative neoplasm	predicted - sensitive	C220 + Ruxolitinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, combination of C220 and Jakafi (ruxolitinib) treatment led to additive effects, resulting in inhibition of proliferation of myeloproliferative neoplasm cell lines expressing JAK2 V617F in culture, and inhibited tumor growth, with a 73% tumor reduction, in a cell line xenograft model (PMID: 32669286).	32669286