IGFBP7 and dexamethasone resistance in acute lymphoblastic leukemia

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)