Correction of Bcl-x splicing improves responses to imatinib in chronic myeloid leukaemia cells and mouse models
Correction of Bcl-x splicing improves responses to imatinib in chronic myeloid leukaemia cells and mouse models
复制标题
纠正 Bcl-x 剪接可改善慢性粒细胞白血病细胞和小鼠模型对伊马替尼的反应
DOI：
10.1111/bjh.16472
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发表时间：
2020-03-19
影响因子：
6.5
通讯作者：
Liu，Jing
中科院分区：
文献类型：
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作者：
Zhang，Jing;Wang，Yan;Liu，Jing
甲磺酸伊马替尼（IM）耐药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剪接是失调的，并参与多种恶性肿瘤的发生和化疗耐药性，包括CML。本研究的目的是纠正Bcl-xin CML的异常剪接，并研究随后的恶性表型变化，特别是对IM的反应。使用体内吗啉代反义寡聚体（vMO）有效地恢复CML细胞中的异常Bcl ‐ x剪接。CCK-8细胞活力测定和流式细胞术显示，恢复Bcl-x剪接增强IM诱导的K562细胞生长抑制和凋亡。此外，在伊马替尼耐药CML细胞系K562/G 01中观察到更显著的类似现象。最后，CML异种移植模型的建立也证明了纠正体内Bcl ‐ x剪接也能增强IM的抗肿瘤作用。我们的研究结果表明，vMO与IM协同作用可以有效地增加CML细胞对IM的体外和体内敏感性，Bcl ‐ x剪接可能成为IM耐药CML化疗增敏靶点的良好候选者。
Imatinib mesylate (IM) resistance has become a major clinical problem for chronic myeloid leukaemia (CML). It is known thatBcl‐xsplicing 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 ofBcl‐xin CML and investigate the subsequent malignant phenotype changes, especially response to IM. The aberrantBcl‐xsplicing in CML cells was effectively restored using vivo‐Morpholino Antisense Oligomer (vMO). CCK‐8 cell viability assay and flow cytometry showed that restoring ofBcl‐xsplicing 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 correctingBcl‐xsplicingin vivocan 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 bothin vitroandin vivo, andBcl‐xsplicing could become good candidates for chemotherapy‐sensitized target in IM‐resistant CML.