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Investigation of IRS2 role on the pathogenesis of myeloproliferative neoplasms JAK2V617F using murine models

Grant number: 16/23191-4
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): April 01, 2017
Effective date (End): January 31, 2021
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Fabíola Traina
Grantee:Juan Luiz Coelho da Silva
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated scholarship(s):19/11747-6 - Deciphering the role of ASXL1 mutations on driving myeloproliferative neoplasm progression, BE.EP.DR

Abstract

The JAK2V617F mutation is identified in the majority of patients with myeloproliferative neoplasms (MPN), and is considered a diagnostic hallmark for these diseases. Additional mutations in MPL and CALR, which participates of JAK/STAT pathways, are diagnostic markers for 80% of JAK2 negatives patients. Inhibitors of JAK / STAT pathway represent a therapeutic advance in MPN treatment, however the failure in inducing complete remission indicates the need of studies that aim to identify alternative pathways. Our group identified that, in HEL cells JAK2V617F, insulin receptor substrate 2 (IRS2) is associated with JAK2, and IRS2 silencing reduces cellular proliferation, induces apoptosis and presents synergic effect with the selective JAK1/2 inhibitor ruxolitinib. We herein propose to identify the IRS2 role in the pathogenesis of MPN using (a) the murine model JAK2V617F knockin and Irs2 knockout (Irs2-/-), (b) systemic MPN model induced by Ba/F3 JAK2V617F, silenced or not for Irs2 and (c) xenotransplant model induced by HEL cells JAK2V617F, silenced or not for IRS2. Murine models will be submitted to evaluation of survival, tumor burden by bioluminescence, evaluation of ex vivo self-renewal and hematopoetic stem cell self-renewal capacities, evaluation of cellular proliferation and apoptosis and/or activation of JAK/STAT, PI3K/AKT/mTOR and MAPK pathways.

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SILVEIRA, DOUGLAS R. A.; QUEK, LYNN; SANTOS, ITAMAR S.; CORBY, ANNA; COELHO-SILVA, JUAN L.; PEREIRA-MARTINS, DIEGO A.; VALLANCE, GRANT; BROWN, BENJAMIN; NARDINELLI, LUCIANA; SILVA, WELLINGTON F.; VELLOSO, ELVIRA D. R. P.; LUCENA-ARAUJO, ANTONIO R.; TRAINA, FABIOLA; PENIKET, ANDY; VYAS, PARESH; REGO, EDUARDO M.; BENDIT, ISRAEL; ROCHA, VANDERSON. Integrating clinical features with genetic factors enhances survival prediction for adults with acute myeloid leukemia. BLOOD ADVANCES, v. 4, n. 10, p. 2339-2350, MAY 26 2020. Web of Science Citations: 0.

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