c-myb is involved in CML progression and is a therapeutic target in the zebrafish CML model

Abstract

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.

Keywords

chronic myeloid leukemia / c-myb / flavopiridol / zebrafish model

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2022 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.