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Correction of Bcl-x splicing improves responses to imatinib in chronic myeloid leukaemia cells and mouse models
Jing Zhang1,2, Yan Wang3,4,5, Shu-Qi Li1,2
1Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
Abstract:
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.
Insights
Restoring abnormal Bcl-x splicing with vivo-Morpholino Antisense Oligomer (vMO) enhances imatinib sensitivity in chronic myeloid leukaemia (CML) cells. This approach improves imatinib
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Imatinib mesylate (IM) resistance is a significant clinical challenge in chronic myeloid leukaemia (CML).
- Deregulation of Bcl-x splicing is implicated in various cancers and chemotherapy resistance, including CML.
- Targeting aberrant splicing offers a potential strategy to overcome drug resistance.
Purpose of the Study:
- To correct abnormal Bcl-x splicing in CML cells.
- To investigate the impact of corrected Bcl-x splicing on CML cell phenotype and IM response.
- To evaluate the efficacy of combining vMO with IM in preclinical CML models.
Main Methods:
- Utilized vivo-Morpholino Antisense Oligomer (vMO) to restore aberrant Bcl-x splicing in CML cells.
- Assessed cell viability and apoptosis using CCK-8 assays and flow cytometry.
- Evaluated therapeutic effects in imatinib-resistant CML cell lines (K562/G01) and a CML xenograft model.
Main Results:
- vMO effectively restored abnormal Bcl-x splicing in CML cells.
- Corrected Bcl-x splicing enhanced IM-induced growth inhibition and apoptosis in K562 cells.
- Significant improvements in IM sensitivity were observed in imatinib-resistant cell lines and in vivo xenograft models.
Conclusions:
- vMO co-administration with IM increases CML cell sensitivity to IM both in vitro and in vivo.
- Targeting Bcl-x splicing represents a promising strategy for overcoming IM resistance in CML.
- Bcl-x splicing modulation could serve as a valuable approach for chemotherapy sensitization in resistant CML.
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