CDK6 coordinates JAK2 V617F mutant MPN via NF-?B and apoptotic networks.
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ABSTRACT:
SUBMITTER: Uras IZ
PROVIDER: S-EPMC6543514 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
Publications
CDK6 coordinates <i>JAK2</i> <sup><i>V617F</i></sup> mutant MPN via NF-κB and apoptotic networks.
Uras Iris Z IZ Maurer Barbara B Nivarthi Harini H Jodl Philipp P Kollmann Karoline K Prchal-Murphy Michaela M Milosevic Feenstra Jelena D JD Zojer Markus M Lagger Sabine S Grausenburger Reinhard R Grabner Beatrice B Holly Raimund R Kavirayani Anoop A Kavirayani Anoop A Bock Christoph C Gisslinger Heinz H Valent Peter P Kralovics Robert R Sexl Veronika V
Blood 20190111 15
Over 80% of patients with myeloproliferative neoplasms (MPNs) harbor the acquired somatic <i>JAK2</i> <sup><i>V617F</i></sup> mutation. JAK inhibition is not curative and fails to induce a persistent response in most patients, illustrating the need for the development of novel therapeutic approaches. We describe a critical role for CDK6 in MPN evolution. The absence of <i>Cdk6</i> ameliorates clinical symptoms and prolongs survival. The CDK6 protein interferes with 3 hallmarks of disease: beside ...[more]
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Project description: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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Project description:BackgroundEvasion from programmed cell death is a hallmark of cancer and can be achieved in cancer cells by overexpression of inhibitor of apoptosis proteins (IAPs). Second mitochondria-derived activator of caspases (SMAC) directly bind to IAPs and promote apoptosis; thus, SMAC mimetics have been investigated in a variety of cancer types. particularly in diseases with high inflammation and NFĸB activation. Given that elevated TNFα levels and NFĸB activation is a characteristic feature of myeloproliferative neoplasms (MPN), we investigated the effect of the SMAC mimetic LCL-161 on MPN cell survival in vitro and disease development in vivo.MethodsTo investigate the effect of the SMAC mimetic LCL-161 in vitro, we utilized murine and human cell lines to perform cell viability assays as well as primary bone marrow from mice or humans with JAK2V617F-driven MPN to interrogate myeloid colony formation. To elucidate the effect of the SMAC mimetic LCL-161 in vivo, we treated a JAK2V617F-driven mouse model of MPN with LCL-161 then assessed blood counts, splenomegaly, and myelofibrosis.ResultsWe found that JAK2V617F-mutated cells are hypersensitive to the SMAC mimetic LCL-161 in the absence of exogenous TNFα. JAK2 kinase activity and NFĸB activation is required for JAK2V617F-mediated sensitivity to LCL-161, as JAK or NFĸB inhibitors diminished the differential sensitivity of JAK2V617F mutant cells to IAP inhibition. Finally, LCL-161 reduces splenomegaly and may reduce fibrosis in a mouse model of JAK2V617F-driven MPN.ConclusionLCL-161 may be therapeutically useful in MPN, in particular when exogenous TNFα signaling is blocked. NFĸB activation is a characteristic feature of JAK2V617F mutant cells and this sensitizes them to SMAC mimetic induced killing even in the absence of TNFα. However, when exogenous TNFα is added, NFĸB is activated in both mutant and wild-type cells, abolishing the differential sensitivity. Moreover, JAK kinase activity is required for the differential sensitivity of JAK2V617F mutant cells, suggesting that the addition of JAK2 inhibitors to SMAC mimetics would detract from the ability of SMAC mimetics to selectively target JAK2V617F mutant cells. Instead, combination therapy with other agents that reduce inflammatory cytokines but preserve JAK2 signaling in mutant cells may be a more beneficial combination therapy in MPN.
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2024-03-29 | GSE255253 | GEO
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| S-EPMC3414675 | biostudies-literature