Investigation of IRS1/IRS2 silencing effects on the phenotype of CD34+ normal primary hematopoietic cells and BCR-ABL+ leukemic cells

• Grant number: 14/06037-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: March 01, 2015
• End date: September 30, 2017
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Fabíola Traina
• Grantee: Renata Scopim Ribeiro
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 16/01639-3 - Investigation of IRS1/IRS2 inhibition in BCR-ABL1 cells using murine models, BE.EP.DR

Abstract

Hematopoiesis is regulated by cytokines and growth factors. The proper action of cytokines and growth factors depends, among other factors, on the action of cytoplasmic adapter proteins such as insulin receptor substrates (IRS). The association of IRS proteins to their receptors results in IRS tyrosine phosphorylation, which creates binding sites that recruit effector proteins involved in MAP kinase and PI3K/AKT cell signaling pathways. The main receptors capable of activating IRS1 and IRS2 are the insulin receptor (IR) and IGF1 receptor (IGF1R). Additionally, IRS2 can be activated by its association with receptors of erythropoietin (EPOR) and thrombopoietin (MPL), and IRS1 can be activated by the cytoplasmic oncoprotein BCR -ABL. MAP kinase and PI3K/AKT pathways are recruited in the normal hematopoiesis and are dysregulated in hematological malignancies, but the involvement of IRS proteins in activation of these signaling pathways in normal and leukemic hematopoiesis has not been elucidated. The aim of this study is to investigate the phenotype of normal hematopoietic CD34+ cells and primary leukemic BCR-ABL+ cells submitted to IRS1 and IRS2 silencing. Normal CD34+ hematopoietic cells and primary BCR-ABL+ cells will be submitted to IRS1/IRS2 inhibition through lentivirus or pharmacological inhibition with NT157, and will be submitted to functional assays of differentiation, proliferation, and/or apoptosis. Modulation of the PI3K/AKT and MAP kinase pathways in cells silenced or not for IRS1/IRS2 will be assessed by Western blotting. (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)

SCOPIM-RIBEIRO, RENATA; MACHADO-NETO, JOAO AGOSTINHO; EIDE, CHRISTOPHER A.; COELHO-SILVA, JUAN LUIZ; FENERICH, BRUNA ALVES; FERNANDES, JAQUELINE CRISTINA; SCHEUCHER, PRISCILA SANTOS; STEVENS, SAMANTHA L. SAVAGE; CAMPOS, PAULA DE MELO; OLALLA SAAD, SARA T.; et al. NT157, an IGF1R-IRS1/2 inhibitor, exhibits antineoplastic effects in pre-clinical models of chronic myeloid leukemia. INVESTIGATIONAL NEW DRUGS, v. 39, n. 3, JAN 2021. (14/06037-6, 13/08135-2, 16/01639-3)

Academic Publications

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

RIBEIRO, Renata Scopim. Investigation of the effects of IGF1R-IRS1/2 pharmacological inhibition on the phenotype of BCR-ABL1+ leukemic cells. 2017. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.