Integrin alphavbeta3 enhances β-catenin signaling in acute myeloid leukemia harboring Fms-like tyrosine kinase-3 internal tandem duplication mutations: implications for microenvironment influence on sorafenib sensitivity

Binding of leukemia cells to the bone marrow extracellular matrix (ECM) through integrins might influence drug response and the survival of acute myeloid leukemia (AML). However, the functions of integrin in AML are needed to be clarified. Data from The Cancer Genome Atlas (TCGA) were retrieved and integrin beta 3 (ITGB3) expression and prognostic significance for AML were analyzed. Integrin alphavbeta3 (alpha v beta 3) in sorafenib sensitivity and signaling pathway of FLT3-ITD AML cells was evaluated in vitro. The level of ITGB3 expression was positively correlated with risk stratification and prognosis of AML patients, especially in cytogenetic-normal patients with Fms-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutation. Integrin alpha v beta 3 decreased sorafenib sensitivity when co-culture of MV4-11 cells and bone marrow stromal cells (BMSCs), and it is crucial for osteopontin (OPN) induced sorafenib insensitivity in FLT3-ITD mutated AML cells. Mechanically, alpha v beta 3 enhance beta-catenin activation through phosphatidylinositol 3-kinase (PI3K)/Akt/Glycogen synthase kinase-3 beta (GSK3 beta) pathway. Moreover, genetic inhibition of beta-catenin by shRNA could increase sorafenib sensitivity in MV4-11 cells. Taken together, our study revealed a novel mechanism in microenvironment influence on sorafenib sensitivity in AML with FLT3-ITD mutation that was caused by activating integrin alpha v beta 3/PI3K/Akt/GSK3 beta/beta-catenin pathway. Integrin alpha v beta 3/beta-catenin could be considered as a new therapeutic target for AML especially for FLT3-ITD mutated AML.