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.
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.
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整合素 alphavbeta3 增强含有 Fms 样酪氨酸激酶 3 内部串联重复突变的急性髓系白血病中的 β-连环蛋白信号传导：微环境对索拉非尼敏感性的影响
DOI：
10.18632/oncotarget.9617
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发表时间：
2016-06-28
期刊：
影响因子：
--
通讯作者：
Kong P
中科院分区：
文献类型：
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作者：
Yi H;Zeng D;Shen Z;Liao J;Wang X;Liu Y;Zhang X;Kong P
白血病细胞通过整合素与骨髓细胞外基质（ECM）结合可能影响急性髓细胞白血病（AML）的药物反应和生存。然而，整合素在AML中的功能需要澄清。检索癌症基因组图谱（TCGA）中的数据，分析整合素β3（ITGB 3）表达及其对AML的预后意义。在体外评估整合素α v β 3（αvβ3）在FLT 3-ITD AML细胞的索拉非尼敏感性和信号通路中的作用。ITGB 3表达水平与AML患者的危险分层和预后呈正相关，尤其是在伴有FLT 3-ITD突变的细胞遗传学正常患者中。整合素αvβ3降低MV 4 -11细胞与骨髓基质细胞（BMSCs）共培养时索拉非尼的敏感性，在FLT 3-ITD突变AML细胞中骨桥蛋白（OPN）诱导索拉非尼不敏感性中起关键作用。在机械上，αvβ3通过磷脂酰肌醇3-激酶（PI 3 K）/Akt/糖原合成酶激酶-3 β（GSK 3 β）途径增强β-连环蛋白活化。此外，通过shRNA对β-catenin的遗传抑制可以增加MV 4 -11细胞中索拉非尼的敏感性。总之，我们的研究揭示了微环境影响FLT 3-ITD突变AML患者索拉非尼敏感性的新机制，其通过激活整合素αvβ3/PI 3 K/Akt/GSK 3 β/β-catenin途径引起。整合素αvβ3/β-catenin可作为AML尤其是FLT 3-ITD突变型AML治疗的新靶点。
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.