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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Autophagy inhibition potentiates ruxolitinib-induced apoptosis in JAK2(V617F) cells

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Machado-Neto, Joao Agostinho [1, 2] ; Coelho-Silva, Juan Luiz [2] ; de Souza Santos, Fabio Pires [3, 4] ; Scheucher, Priscila Santos [2] ; Campregher, Paulo Vidal [3, 4] ; Hamerschlak, Nelson [3] ; Rego, Eduardo Magalhaes [2] ; Traina, Fabiola [2]
Total Authors: 8
[1] Univ Sao Paulo, Dept Pharmacol, Inst Biomed Sci, Sao Paulo - Brazil
[2] Univ Sao Paulo, Dept Med Images Hematol & Clin Oncol, Ribeirao Preto Med Sch, Av Bandeirante, BR-3900 Ribeirao Preto, SP - Brazil
[3] Hosp Israelita Albert Einstein Sao Paulo, Ctr Oncol & Hematol Familia Dayan Daycoval, Sao Paulo - Brazil
[4] Hosp Israelita Albert Einstein Sao Paulo, Inst Ensino & Pesquisa, Sao Paulo - Brazil
Total Affiliations: 4
Document type: Journal article
Source: INVESTIGATIONAL NEW DRUGS; v. 38, n. 3, p. 733-745, JUN 2020.
Web of Science Citations: 0

JAK2(V617F) can mimic growth factor signaling, leading to PI3K/AKT/mTOR activation and inhibition of autophagy. We hypothesized that selective inhibition of JAK1/2 by ruxolitinib could induce autophagy and limit drug efficacy in myeloproliferative neoplasms (MPN). Therefore, we investigated the effects of ruxolitinib treatment on autophagy-related genes and cellular processes, to determine the potential benefit of autophagy inhibitors plus ruxolitinib in JAK2(V617F) cells, and to verify the frequency and clinical impact of autophagy-related gene mutations in patients with MPNs. In SET2 JAK2(V617F) cells, ruxolitinib treatment induced autophagy and modulated 26 out of 79 autophagy-related genes. Ruxolitinib treatment reduced the expressions of important autophagy regulators, including mTOR/p70S6K/4EBP1 and the STAT/BCL2 axis, in a dose- and time-dependent manner. Pharmacological inhibition of autophagy was able to significantly suppress ruxolitinib-induced autophagy and increased ruxolitinib-induced apoptosis. Mutations in autophagy-related genes were found in 15.5% of MPN patients and were associated with increased age and a trend towards worse survival. In conclusion, ruxolitinib induces autophagy in JAK2(V617F) cells, potentially by modulation of mTOR-, STAT- and BCL2-mediated signaling. This may lead to inhibition of apoptosis. Our results suggest that the combination of ruxolitinib with pharmacological inhibitors of autophagy, such as chloroquine, may be a promising strategy to treat patients with JAK2(V617F)-mutated MPNs. (AU)

FAPESP's process: 14/50947-7 - INCT 2014: in Stem Cell and Cell Therapy
Grantee:Dimas Tadeu Covas
Support type: Research Projects - Thematic Grants
FAPESP's process: 14/23092-0 - Investigation of IRS2 protein function in hematopoietic cells
Grantee:João Agostinho Machado Neto
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 17/19864-6 - Investigation of IRS1 and IRS2 function in normal hematopoiesis and myelodysplastic syndrome using murine models and human hematopoietic stem cells
Grantee:Fabíola Traina
Support type: Regular Research Grants
FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
Grantee:Dimas Tadeu Covas
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC