Functional investigation of IRS2 in BCR-ABL1 negative chronic myeloproliferative neoplasms

• Grant number: 15/02200-2
• Support Opportunities: Regular Research Grants
• Duration: April 01, 2016 - March 31, 2018
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Fabíola Traina
• Grantee: Fabíola Traina
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The BCR-ABL1 negative chronic myeloproliferative neoplasms (MPN) are characterized by increased cellular proliferation with preserved terminal myeloid differentiation. In most cases, the activation of cell proliferation is caused by an increased tyrosine kinase activity of specific proteins. However, patients' molecular heterogeneity and the incomplete clinical responses observed in part of the cases using the current treatments suggest that additional mechanisms, such as unknown protein interactions and new mutations, can be involved in the pathophysiology of MPN. Insulin receptor substrate 2 (IRS2) is an adaptor cytoplasmic protein initially identified due to its role in insulin signaling, but may also interact with EPOR, MPL e IGF1R and may activate JAK/STAT, PI3K/Akt/mTOR and MAPK signaling. Recently, our research group has identified the protein interaction JAK2/IRS2 in JAK2V617F cells. The aims of this study are to evaluate the effect of combined treatment of ruxolitinib with IRS2 or mTOR inhibitors in JAK2V617F cells and to establish the murine knockout Irs2 model. Leukemia cell lines and primary cells will be used for functional studies. Methods will include evaluation of cell survival and signaling pathways in leukemia cell lines submitted or not to different conditions including protein silencing by gene therapy tools and/or use of specific inhibitor compounds, establishment of murine knockout Irs2 and evaluation of hematopoiesis in this model. (AU)

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)

MACHADO-NETO, JOAO AGOSTINHO; FENERICH, BRUNA ALVES; SCOPIM-RIBEIRO, RENATA; EIDE, CHRISTOPHER A.; COELHO-SILVA, JUAN LUIZ; PORTO DECHANDT, CARLOS ROBERTO; FERNANDES, JAQUELINE CRISTINA; NUNES RODRIGUES ALVES, ANA PAULA; SCHEUCHER, PRISCILA SANTOS; SIMOES, BELINDA PINTO; et al. Metformin exerts multitarget antileukemia activity in JAK2(V617F)-positive myeloproliferative neoplasms. CELL DEATH & DISEASE, v. 9, FEB 22 2018. (15/02200-2, 14/23092-0)

FERNANDES, JAQUELINE CRISTINA; FENERICH, BRUNA ALVES; ALVES-SILVA, ANTONIO BRUNO; FONSECA, NATASHA PEIXOTO; COELHO-SILVA, JUAN LUIZ; SCHEUCHER, PRISCILA SANTOS; REGO, EDUARDO MAGALHAES; FIGUEIREDO-PONTES, LORENA LOBO; MACHADO-NETO, JOAO AGOSTINHO; TRAINA, FABIOLA. Differential cytotoxic activity of pharmacological inhibitors of IGF1R-related pathways in JAK2(V617F) driven cells. TOXICOLOGY IN VITRO, v. 83, p. 7-pg., 2022-05-26. (13/08135-2, 17/19864-6, 15/02200-2, 16/14049-0, 19/23864-7)

FENERICH, BRUNA ALVES; FERNANDES, JAQUELINE CRISTINA; RODRIGUES ALVES, ANA PAULA NUNES; COELHO-SILVA, JUAN LUIZ; SCOPIM-RIBEIRO, RENATA; SCHEUCHER, PRISCILA SANTOS; EIDE, CHRISTOPHER A.; TOGNON, CRISTINA E.; DRUKER, BRIAN J.; REGO, EDUARDO MAGALHAES; et al. NT157 has antineoplastic effects and inhibits IRS1/2 and STAT3/5 in JAK2(V617F)-positive myeloproliferative neoplasm cells. SIGNAL TRANSDUCTION AND TARGETED THERAPY, v. 5, n. 1, JAN 24 2020. (15/09324-9, 15/02200-2, 13/08135-2, 14/50947-7)