Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
Jiangxi Province Key Laboratory of Laboratory Medicine, Nanchang, China.
Br J Haematol. 2020 Jun;189(6):1141-1150. doi: 10.1111/bjh.16472. Epub 2020 Mar 19.
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.
甲磺酸伊马替尼（IM）耐药已成为慢性髓系白血病（CML）的主要临床问题。已知 Bcl-x 剪接失调，参与多种恶性肿瘤的起始和化疗耐药，包括 CML。本研究旨在纠正 CML 中 Bcl-x 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 vivo-Morpholino Antisense Oligomer（vMO）有效地恢复了 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，恢复 Bcl-x 剪接增加了 IM 诱导的 K562 细胞生长抑制和凋亡。此外，在伊马替尼耐药的 CML 细胞系 K562/G01 中观察到更明显的类似现象。最后，建立 CML 异种移植模型也证明了体内纠正 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 联合使用可以有效地提高体外和体内 CML 细胞对 IM 的敏感性，Bcl-x 剪接可能成为伊马替尼耐药 CML 中化疗增敏的候选靶标。
