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|Ref Type||Journal Article|
|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.|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|C220||PRMT5 Inhibitor 14||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||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 JAK V617F in culture, and inhibited tumor growth, with a 71% tumor reduction, in a cell line xenograft model (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|
|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||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|