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Full text
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| Author(s): |
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
|
| Affiliation: | [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
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| Document type: |
Journal article
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| Source: |
INVESTIGATIONAL NEW DRUGS;
v. 38,
n. 3,
p. 733-745,
JUN 2020.
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| Web of Science Citations: |
0
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| Abstract |
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) |
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| FAPESP's process: |
14/50947-7 - INCT 2014: in Stem Cell and Cell Therapy
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| Grantee: | Dimas Tadeu Covas |
| Support type: |
Research Projects - Thematic Grants
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| FAPESP's process: |
14/23092-0 - Investigation of IRS2 protein function in hematopoietic cells
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| Grantee: | João Agostinho Machado Neto |
| Support type: |
Scholarships in Brazil - Post-Doctorate
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| 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
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| Grantee: | Fabíola Traina |
| Support type: |
Regular Research Grants
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|
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| 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
|
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