Imatinib mesylate (IM) resistance has become a major clinical problem for chronic myeloid leukaemia (CML). It is known that Bcl‐x splicing is deregulated and is involved in multiple malignant cancer initiation and chemotherapy resistance, including CML. The aim of the present study was to correct the abnormal splicing of Bcl‐x in CML and investigate the subsequent malignant phenotype changes, especially response to IM. The aberrant Bcl‐x splicing in CML cells was effectively restored using vivo‐Morpholino Antisense Oligomer (vMO). CCK‐8 cell viability assay and flow cytometry showed that restoring of Bcl‐x splicing increases IM‐induced growth inhibition and apoptosis of K562 cells. Moreover, a more significant similar phenomenon was observed in imatinib‐resistant CML cell lines K562/G01. Finally, establishment of CML xenograft model had also proved that correcting Bcl‐x splicing in vivo can also enhance the anti‐tumor effect of IM. Our findings suggest that vMO co‐operating with IM can effectively increase the sensitivity of CML cells to IM both in vitro and in vivo , and Bcl‐x splicing could become good candidates for chemotherapy‐sensitized target in IM‐resistant CML.

中文翻译：

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Bcl-x剪接的校正可改善对慢性粒细胞白血病细胞和小鼠模型中伊马替尼的反应。

甲磺酸伊马替尼（IM）的耐药性已成为慢性粒细胞白血病（CML）的主要临床问题。众所周知，Bcl-x剪接被放松，并参与多种恶性肿瘤的起始和化疗耐药性，包括CML。本研究的目的是纠正CML中Bcl-x的异常剪接，并研究随后的恶性表型变化，尤其是对IM的反应。使用vivo-Morpholino反义寡聚物（vMO）有效恢复了CML细胞中异常的Bcl-x剪接。CCK-8细胞活力测定和流式细胞术表明Bcl-x的恢复剪接增加IM诱导的K562细胞生长抑制和凋亡。此外，在对伊马替尼耐药的CML细胞株K562 / G01中观察到了更明显的相似现象。最后，建立CML异种移植模型还证明了在体内纠正Bcl-x剪接也可以增强IM的抗肿瘤作用。我们的研究结果表明vMO与IM配合可以有效提高CML细胞在体外和体内对IM的敏感性，并且Bcl-x剪接可能成为IM耐药CML化疗敏感靶点的良好候选者。