MXD1 regulates the imatinib resistance of chronic myeloid leukemia cells by repressing BCR-ABL1 expression
Chen Huan1, Lou Jin1, Wang Heng1
1Shenzhen Bone Marrow Transplantation Public Service Platform, Shenzhen Institute of Hematology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
Abstract:
Tyrosine kinase inhibitors have achieved unprecedented efficacy in the treatment of chronic myeloid leukemia (CML); however, imatinib resistance has emerged as a major problem in the clinic. Because the overexpression of BCR-ABL1 critically contributes to CML pathogenesis and drug resistance, targeting the regulation of BCR-ABL1 gene expression may be an alternative therapeutic strategy. In this study, we found that the transcriptional repressor MXD1 showed low expression in CML patients and was negatively correlated with BCR-ABL1. Overexpression of MXD1 markedly inhibited the proliferation of K562 cells and sensitized the imatinib-resistant K562/G01 cell line to imatinib, with decreased BCR-ABL1 mRNA and protein expression. Further investigation using reporter gene analysis showed that MXD1 significantly inhibited the transcriptional activity of the BCR-ABL1 gene promoter. Taken together, these data show that MXD1 functions as a negative regulator of BCR-ABL1 expression and subsequently inhibits proliferation and sensitizes CML cells to imatinib treatment.
Insights
The transcriptional repressor MXD1, when overexpressed, inhibits chronic myeloid leukemia (CML) cell proliferation and sensitizes imatinib-resistant cells to treatment by reducing BCR-ABL1 expression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Tyrosine kinase inhibitors (TKIs) are effective for chronic myeloid leukemia (CML).
- Imatinib resistance is a significant clinical challenge in CML treatment.
- BCR-ABL1 overexpression is a key driver of CML pathogenesis and drug resistance.
Purpose of the Study:
- To investigate MXD1 as a potential therapeutic target for CML.
- To explore the role of MXD1 in regulating BCR-ABL1 gene expression.
- To assess MXD1's effect on CML cell proliferation and imatinib sensitivity.
Main Methods:
- Analysis of MXD1 expression in CML patients.
- Overexpression of MXD1 in K562 and K562/G01 cell lines.
- Measurement of BCR-ABL1 mRNA and protein levels.
- Reporter gene assays to assess promoter activity.
Main Results:
- MXD1 expression was low and negatively correlated with BCR-ABL1 in CML patients.
- MXD1 overexpression inhibited K562 cell proliferation.
- MXD1 sensitized imatinib-resistant K562/G01 cells to imatinib.
- MXD1 overexpression decreased BCR-ABL1 mRNA and protein levels.
- MXD1 significantly inhibited the transcriptional activity of the BCR-ABL1 promoter.
Conclusions:
- MXD1 acts as a negative regulator of BCR-ABL1 expression.
- MXD1 demonstrates potential as a therapeutic strategy for CML, particularly in overcoming imatinib resistance.
- Targeting MXD1 could offer a novel approach to CML treatment by modulating BCR-ABL1.
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