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

• Grant number: 16/23191-4
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: April 01, 2017
• End date: March 31, 2021
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Fabíola Traina
• Grantee: Juan Luiz Coelho da Silva
• Host 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

(6)

(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)

PEREIRA-MARTINS, DIEGO A.; WEINHAUSER, ISABEL; COELHO-SILVA, JUAN LUIZ; FRANCA-NETO, PEDRO L.; ALMEIDA, LUCIANA Y.; BIANCO, THIAGO M.; SILVA, CLEIDE L.; FRANCA, RAFAEL F.; TRAINA, FABIOLA; REGO, EDUARDO M.; et al. MLL5 improves ATRA driven differentiation and promotes xenotransplant engraftment in acute promyelocytic leukemia model. CELL DEATH & DISEASE, v. 12, n. 4, APR 6 2021. (16/23191-4, 17/23117-1, 13/08135-2, 15/09228-0)

COELHO-SILVA, JUAN L.; SILVEIRA, DOUGLAS R. A.; PEREIRA-MARTINS, DIEGO A.; ROJAS, CESAR A. O.; LUCENA-ARAUJO, ANTONIO R.; REGO, EDUARDO M.; MACHADO-NETO, JOAO A.; BENDIT, ISRAEL; ROCHA, VANDERSON; TRAINA, FABIOLA. Molecular-Based Score inspired on metabolic signature improves prognostic stratification for myelodysplastic syndrome. SCIENTIFIC REPORTS, v. 11, n. 1, JAN 18 2021. (14/50947-7, 17/23117-1, 13/08135-2, 16/23191-4, 17/19864-6)

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.; et al. 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. (16/23191-4, 17/23117-1)

PEREIRA-MARTINS, DIEGO A.; WEINHAUSER, ISABEL; COELHO-SILVA, JUAN LUIZ; FRANCA-NETO, PEDRO L.; ALMEIDA, LUCIANA Y.; BIANCO, THIAGO M.; SILVA, CLEIDE L.; FRANCA, RAFAEL F.; TRAINA, FABIOLA; REGO, EDUARDO M.; et al. MLL5 improves ATRA driven differentiation and promotes xenotransplant engraftment in acute promyelocytic leukemia model. CELL DEATH & DISEASE, v. 12, n. 4, p. 14-pg., 2021-04-06. (13/08135-2, 17/23117-1, 15/09228-0, 16/23191-4)

PEREIRA-MARTINS, DIEGO A.; COELHO-SILVA, JUAN L.; WEINHAUSER, ISABEL; FRANCA-NETO, PEDRO L.; SILVEIRA, DOUGLAS R.; ORTIZ, CESAR; MOREIRA-AGUIAR, AMANDA; LIMA, MARINUS M.; KOURY, LUISA C.; DE MELO, RAUL A.; et al. Clinical significance of mitochondrial DNA content in acute promyelocytic leukaemia. British Journal of Haematology, v. 200, n. 2, p. 5-pg., 2022-10-20. (13/08135-2, 16/23191-4, 15/09228-0, 17/23117-1)

SILVEIRA, DOUGLAS R. A.; COELHO-SILVA, JUAN L.; SILVA, WELLINGTON F.; VALLANCE, GRANT; PEREIRA-MARTINS, DIEGO A.; MADEIRA, MARIA I. A.; FIGUEREDO-PONTES, LORENA L.; VELLOSO, ELVIRA D. R. P.; SIMOES, BELINDA P.; PENIKET, ANDY; et al. A multicenter comparative acute myeloid leukemia study: can we explain the differences in the outcomes in resource-constrained settings?. Leukemia & Lymphoma, v. 62, n. 1, p. 147-157, JAN 2 2021. (16/23191-4, 17/23117-1)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

SILVA, Juan Luiz Coelho da. Clinical and molecular prospection of new therapeutic targets for myeloid neoplasms. 2021. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.