Research Papers:

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

Hai Yi _, Dongfeng Zeng, Zhaohua Shen, Jun Liao, Xiaoguo Wang, Yao Liu, Xi Zhang and Peiyan Kong

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:40387-40397. https://doi.org/10.18632/oncotarget.9617

Metrics: PDF 2586 views  |   HTML 2624 views  |   ?  


Hai Yi1,2, Dongfeng Zeng1, Zhaohua Shen1, Jun Liao1, Xiaoguo Wang1, Yao Liu1, Xi Zhang1, Peiyan Kong1

1Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China

2Department of Hematology, General Hospital of Chengdu Military Region, Chengdu, 610083, People's Republic of China

Correspondence to:

Peiyan Kong, email: [email protected]

Keywords: integrin, acute myeloid leukemia, Fms-like tyrosine kinase-3 internal tandem duplication, β-catenin, drug sensitivity

Received: October 29, 2015    Accepted: May 06, 2016    Published: May 26, 2016


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 β3 (ITGB3) expression and prognostic significance for AML were analyzed. Integrin alphavbeta3 (αvβ3) 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 αvβ3 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, αvβ3 enhance β-catenin activation through phosphatidylinositol 3-kinase (PI3K)/Akt/Glycogen synthase kinase-3 beta (GSK3β) pathway. Moreover, genetic inhibition of β-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 αvβ3/PI3K/Akt/GSK3β/β-catenin pathway. Integrin αvβ3/β-catenin could be considered as a new therapeutic target for AML especially for FLT3-ITD mutated AML.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 9617