Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia
Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia
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DOI：
10.1182/blood.2019001417
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发表时间：
2020-07-09
期刊：
影响因子：
20.3
通讯作者：
Kim, Yong-Mi
中科院分区：
文献类型：
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作者：
Gang, Eun Ji;Kim, Hye Na;Kim, Yong-Mi
对多模式化疗的耐药性继续限制急性淋巴细胞白血病（ALL）的预后。这部分是通过称为粘附介导的耐药性的过程发生的，该过程依赖于ALL细胞通过粘附分子（包括整合素）粘附到基质。整合素α 6与ALL的微小残留病和ALL细胞向中枢神经系统的迁移有关。然而，尚未在化疗耐药性的背景下对其进行评价。在这里，我们表明，抗人α 6阻断抗体P5G10诱导细胞凋亡的原代ALL细胞在体外和体外化疗或酪氨酸激酶抑制原代ALL细胞的敏感性。我们使用鼠BCR-ABL1（+）B细胞ALL细胞中α 6的条件性敲除模型进一步分析了α 6相关凋亡的潜在机制，并表明α 6缺陷型ALL细胞发生凋亡。体内α 6缺失联合酪氨酸激酶抑制剂（TKI）治疗在酪氨酸根除ALL方面比单独使用TKI（尼洛替尼）治疗更有效。蛋白质组学分析显示，小鼠ALL中α 6缺失与Src信号传导的变化相关，包括磷酸化林恩（pTyr 507）和Fyn（pTyr 530）的上调。因此，我们的数据支持α 6作为ALL的新治疗靶点。
Resistance to multimodal chemotherapy continues to limit the prognosis of acute lymphoblastic leukemia (ALL). This occurs in part through a process called adhesion-mediated drug resistance, which depends on ALL cell adhesion to the stroma through adhesion molecules, including integrins. Integrin alpha 6 has been implicated in minimal residual disease in ALL and in the migration of ALL cells to the central nervous system. However, it has not been evaluated in the context of chemotherapeutic resistance. Here, we show that the anti-human alpha 6-blocking Ab P5G10 induces apoptosis in primary ALL cells in vitro and sensitizes primary ALL cells to chemotherapy or tyrosine kinase inhibition in vitro and in vivo. We further analyzed the underlying mechanism of alpha 6-associated apoptosis using a conditional knockout model of alpha 6 in murine BCR-ABL1(+) B-cell ALL cells and showed that alpha 6-deficient ALL cells underwent apoptosis. In vivo deletion of alpha 6 in combination with tyrosine kinase inhibitor (TKI) treatment was more effective in tyrosine eradicating ALL than treatment with a TKI (nilotinib) alone. Proteomic analysis revealed that alpha 6 deletion in murine ALL was associated with changes in Src signaling, including the upregulation of phosphorylated Lyn (pTyr507) and Fyn (pTyr530). Thus, our data support alpha 6 as a novel therapeutic target for ALL.