title: 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.
abstract: 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.
authors.affiliation: Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.|Department of Hematology, General Hospital of Chengdu Military Region, Chengdu, 610083, People's Republic of China.
authors.forename: Hai
authors.initials: H
authors.lastname: Yi
authors.affiliation: Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Zeng
authors.affiliation: Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Liao
authors.affiliation: Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
authors.forename: Xiaoguo
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
authors.forename: Peiyan
authors.initials: P
authors.lastname: Kong
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D053495:Osteopontin / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011379:Prognosis; D012306:Risk; D015398:Signal Transduction; D000077157:Sorafenib; D059016:Tumor Microenvironment; D051176:beta Catenin / Q000378:metabolism*; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D039302:Integrin alphaVbeta3; D010671:Phenylurea Compounds; C506895:SPP1 protein, human; D051176:beta Catenin; D053495:Osteopontin; D009536:Niacinamide; D000077157:Sorafenib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
keywords: Fms-like tyrosine kinase-3 internal tandem duplication; acute myeloid leukemia; drug sensitivity; integrin; β-catenin