Open Accessc‐myb is involved in CML progression and is a therapeutic target in the zebrafish CML model
Author(s) -
Ye Yin,
Yang Xiaojun,
Li Feifei,
Liu Wei,
Zhang Wenqing,
Huang Zhibin
Publication year - 2024
Publication title -
animal models and experimental medicine
Language(s) - English
Resource type - Journals
ISSN - 2576-2095
DOI - 10.1002/ame2.12282
Subject(s) - myb , imatinib , cancer research , zebrafish , myeloid leukemia , biology , transgene , transcription factor , gene , genetics
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.