IGFBP7 and dexamethasone resistance in acute lymphoblastic leukemia

• Grant number: 17/03239-5
• Support Opportunities: Scholarships in Brazil - Master
• Start date: June 01, 2017
• End date: February 28, 2019
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: José Andrés Yunes
• Grantee: Leonardo Luís Artico
• Host Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil

Abstract

Acute Lymphoblastic Leukemia (ALL) is the leading cancer in children. Several studies show that the interactions between leukemic blasts and bone marrow stromal cells (OM) contribute to the resistance of ALL to chemo. In the previous work, we verified that leukemic cells secrete several proteins, among them IGFBP7, which together with their ligands (insulin, IGF-1 and IGF-2) stimulate MO cells to produce asparagine, creating a dynamic contrary to the action of L-asparaginase (chemotherapeutic drug used in the treatment of ALL). However, preliminary results lead us to believe that IGFBP7 may be acting in an autocrine and stromal independent manner, in promoting the resistance of ALL to chemotherapeutics. IGFBP7 was initially described as an adhesion factor, capable of interacting with components of the extracellular matrix. IGFBP7 was then interacted with integrins. Integrins participate in drug resistance in ALL, so that the activation of integrins may be one of the resistance mechanisms triggered by IGFBP7. Based on preliminary results, this project proposes to characterize the mechanism by which IGFBP7 promotes resistance to dexamethasone in leukemic cells. More specifically, it is intended to submit ALL cells to the presence or absence of IGFBP7, then: (1) identify altered gene sets, (2) check for activation of insulin signal transduction pathways / IGFs and integrins (AKT, ERK, IRS, FAK, src), (3) to assess nuclear translocation of the glucocorticoid receptor (GR), and (4) verify whether neutralization or silencing of B1 integrin interferes proliferation and resistance to dexamethasone IGFBP7-dependent. (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)

CURY, NATHALIA MORENO; CAPITAO, REBECA MONIQUE; BORGES DE ALMEIDA, RENAN DO CANTO; ARTICO, LEONARDO LUIS; CORREA, JULIANA RONCHI; SIMAO DOS SANTOS, ERIC FRANCISCO; YUNES, JOSE ANDRES; DUARTE CORREIA, CARLOS ROQUE. Synthesis and evaluation of 2-carboxy indole derivatives as potent and selective anti-leukemic agents. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 181, NOV 1 2019. (13/07600-3, 17/02400-7, 14/25770-6, 17/03239-5, 17/14737-6, 14/08247-8)

CANEVAROLO, RAFAEL RENATINO; DE SOUZA MELO, CAROLINA PEREIRA; CURY, NATHALIA MORENO; ARTICO, LEONARDO LUIZ; CORREA, JULIANA RONCHI; LAU, YANCA TONHASCA; MARIANO, SAMARA SOUSA; SUDALAGUNTA, PRANEETH REDDY; BRANDALISE, SILVIA REGINA; DE MATTOS ZERI, ANA CAROLINA; et al. Glutathione levels are associated with methotrexate resistance in acute lymphoblastic leukemia cell lines. FRONTIERS IN ONCOLOGY, v. 12, p. 18-pg., 2022-12-01. (12/11952-0, 14/08247-8, 08/10034-1, 09/04167-1, 17/02400-7, 17/03239-5)

Academic Publications

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

ARTICO, Leonardo Luís. IGFBP7 as a new therapeutic target in acute lymphoblastic leukemia. 2019. Master's Dissertation - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia Campinas, SP.