Alternative splicing of Ikaros regulates the FUT4/LeX-α5β1 integrin-FAK axis in acute lymphoblastic leukemia.
Alternative splicing of Ikaros regulates the FUT4/LeX-α5β1 integrin-FAK axis in acute lymphoblastic leukemia.
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DOI：
10.1016/j.bbrc.2019.01.064
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发表时间：
2019-02
影响因子：
3.1
通讯作者：
Lijun Yi;Qinghua Hu;Jing Zhou;Zhiqiang Liu;Hong Li
中科院分区：
文献类型：
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作者：
Lijun Yi;Qinghua Hu;Jing Zhou;Zhiqiang Liu;Hong Li
揭示急性淋巴细胞白血病（acute lymphoblastic leukemia， ALL）复发的机制是改善ALL预后的关键，也是一项巨大的挑战。基于甘聚糖的相互作用在免疫监视、细胞-细胞粘附和细胞-基质相互作用中起着至关重要的作用，导致肿瘤治疗失败。然而，对白血病发展所必需的聚糖及其上游致癌驱动因子的调控机制很少报道。在这里，我们证明了LeX，一个很好表征的癌症相关的聚糖表位，在ALL的驱动致癌Ikaros亚型（IK6）的控制下，通过糖基化α5β1整合素加强了细胞-基质的相互作用。通过分析Ikaros的表达谱和临床样本中FUT4/LeXin的表达水平，我们发现FUT4/LeXin与功能失调的Ikaros亚型呈正相关。IK1 （Full length Ikaros）作为转录抑制因子调控FUT4水平，而IK6消除野生型Ikaros介导的转录抑制，导致FUT4表达水平升高。此外，我们发现FUT4可以激活α5β1介导的序列信号转导，并通过增加糖基化加速白血病细胞中整合素α5β1与细胞外基质（ECM）中纤维连接蛋白的粘附和侵袭。总之，我们的研究为Ikaros突变诱导ALL细胞侵袭的机制提供了新的见解，并为阻断LeXin联合普通化疗治疗耐药ALL提供了潜在的策略。
Unveiling the mechanism of the relapse of acute lymphoblastic leukemia (ALL) is the key to improve the prognosis of ALL and remains a huge challenge. Glycan-based interactions play a vital role in immune surveillance, cell-cell adhesion and cell-matrix interaction, contributing to treatment failure in tumor. However, the glycan essential for leukemia development and its upstream regulatory mechanism by oncogenic drivers were rarely reported. Here, we demonstrated that LeX, a well-characterized cancer-related glycan epitope, strengthened the cell-matrix interaction via glycosylating α5β1 integrin under the control of the driver oncogenic Ikaros isoform (IK6) in ALL. By analyzing the expression profile of Ikaros and the level of FUT4/LeXin clinical samples, we found that FUT4/LeXwas positively correlated with dysfunctional Ikaros isoforms. IK1 (Full length Ikaros) regulates the level of FUT4 as a transcription repressor, while IK6 abolished the wild-type Ikaros mediated transcriptional repression and resulted in higher level of FUT4 expression. Moreover, we demonstrated that FUT4 could activate α5β1-mediated sequential signal transduction and accelerate adhesion and invasion between integrin α5β1 in leukemia cells and fibronectin in extracellular matrix (ECM) via increasing glycosylation. Together, our study provides a new insight into the mechanisms by which Ikaros mutation induced ALL cells invasion and a potential strategy for drug-resistance ALL by blocking LeXin combination with common chemotherapy.