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Published on: July 19, 2024
c-myb is involved in CML progression and is a therapeutic target in the zebrafish CML model
Yin Ye1, Xiaojun Yang1, Feifei Li1
1Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, China.
Background:
Despite the success of tyrosine kinase inhibitors in chronic myeloid leukemia (CML) therapy, CML still faces the challenges of drug resistance and progression to blast crisis. Twenty-five percent of patients have imatinib resistance and treatment difficulties due to heterogeneity after progression, but little is known about the mechanism. A key transcription factor in hematopoiesis, MYB, has been reported to increase abnormally in several types of aggressive blood disorders including CML.
Methods:
This study used a zebrafish model to explore the relationship between BCR/ABL1 and c-myb in CML progression. A CML zebrafish model was crossed with a c-myb hyperactivity transgenic line.
Results:
It was found that both exogenous BCR/ABL1 and c-myb could up-regulate the expression of neutrophil-related genes. More seriously, neutrophil accumulation was observed when BCR/ABL1 was combined with c-myb overexpression. Further studies showed that c-myb may be one of the downstream targets of BCR/ABL1 and the effect of BCR/ABL1 on neutrophils was c-myb dependent. Taking advantage of this inheritable in vivo model, it was shown that a combination of imatinib and flavopiridol, a cyclin-dependent kinase inhibitor targeting MYB, could more effectively alleviate the aggressive phenotype of the double transgene line.
Conclusion:
In summary, this study suggests that c-myb acts downstream of BCR/ABL1 and is involved in CML progression and is therefore a risk factor and a valuable target for the treatment of CML progression. The model used in the study could be helpful in high-throughput drug screening in CML transformation.
Insights
Chronic myeloid leukemia (CML) progression involves BCR/ABL1 and MYB. Targeting MYB with flavopiridol alongside imatinib may improve CML treatment by inhibiting MYB
Area of Science:
- Hematology
- Molecular Biology
- Cancer Research
Background:
- Chronic myeloid leukemia (CML) treatment faces challenges like drug resistance and progression to blast crisis.
- MYB, a transcription factor crucial for hematopoiesis, is abnormally elevated in aggressive blood disorders, including CML.
- Mechanisms underlying CML progression and imatinib resistance remain incompletely understood.
Purpose of the Study:
- To investigate the relationship between BCR/ABL1 and c-MYB in CML progression using a zebrafish model.
- To elucidate the role of c-MYB as a downstream target of BCR/ABL1 in CML pathogenesis.
Main Methods:
- Development of a CML zebrafish model by crossing BCR/ABL1 transgenic fish with c-MYB hyperactivity transgenic fish.
- Analysis of neutrophil-related gene expression and neutrophil accumulation in response to BCR/ABL1 and c-MYB.
- Evaluation of combination therapy with imatinib and flavopiridol (a MYB-targeting inhibitor) in the zebrafish model.
Main Results:
- Both BCR/ABL1 and c-MYB up-regulate neutrophil-related genes.
- Combined BCR/ABL1 and c-MYB overexpression leads to significant neutrophil accumulation.
- c-MYB acts downstream of BCR/ABL1, mediating its effect on neutrophils.
- Combination therapy with imatinib and flavopiridol effectively reduced the aggressive phenotype in the double transgene zebrafish model.
Conclusions:
- c-MYB is a downstream target of BCR/ABL1 and plays a critical role in CML progression.
- c-MYB represents a potential therapeutic target for overcoming CML progression and drug resistance.
- The developed zebrafish model is valuable for high-throughput drug screening in CML transformation.
