Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, China.
Animal Model Exp Med. 2024 Apr;7(2):136-144. doi: 10.1002/ame2.12282. Epub 2022 Oct 27.
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.
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.
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.
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.
尽管酪氨酸激酶抑制剂在慢性髓性白血病（CML）治疗中取得了成功，但 CML 仍然面临着耐药性和进展为急变期的挑战。25%的患者由于进展后的异质性而对伊马替尼产生耐药性和治疗困难，但对其机制知之甚少。造血中的关键转录因子 MYB 已被报道在包括 CML 在内的几种侵袭性血液疾病中异常增加。
本研究使用斑马鱼模型来探讨 CML 进展中 BCR/ABL1 和 c-myb 之间的关系。将 CML 斑马鱼模型与 c-myb 过度活跃的转基因系进行杂交。
发现外源性 BCR/ABL1 和 c-myb 均可上调中性粒细胞相关基因的表达。更严重的是，当 BCR/ABL1 与 c-myb 过表达结合时，观察到中性粒细胞的积累。进一步的研究表明，c-myb 可能是 BCR/ABL1 的下游靶标之一，BCR/ABL1 对中性粒细胞的作用依赖于 c-myb。利用这种可遗传的体内模型，表明伊马替尼和 flavopiridol（一种针对 MYB 的细胞周期蛋白依赖性激酶抑制剂）的联合使用可以更有效地缓解双转基因系的侵袭性表型。
综上所述，本研究表明 c-myb 作为 BCR/ABL1 的下游分子发挥作用，参与 CML 的进展，因此是 CML 进展的风险因素和有价值的治疗靶点。该研究中使用的模型可有助于 CML 转化的高通量药物筛选。
