Pei Han Zhong, Guo Yao, Zhao Yuming, Zhang Dengyang, Chang Zhiguang, Zhou Jingfeng, Baek Suk-Hwan, Zhao Zhizhuang Joe, Chen Chun, Chen Yun
Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China.
International Cancer Center, Department of Hematology and Oncology, Hematology Institution of Shenzhen University, Shenzhen University General Hospital, Department of Pharmacology, School of Basic Medical Sciences, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China.
Cancer Lett. 2025 Jan 3;611:217446. doi: 10.1016/j.canlet.2025.217446.
FLT3 mutations are present in one third of patients with Acute myeloid leukemia (AML) and stand as an attractive therapeutic target. Although FLT3 inhibitors demonstrate clinical efficacy, the drug resistance remains challenging attributed to multiple mechanisms. In this study, we found that tyrosine kinase inhibitors (TKIs) targeting FLT3 prompt p53 degradation in AML cells with FLT3-ITD through ubiquitination. STAT5 phosphorylation facilitates its nuclear localization, leading to competitive interactions among STAT5, MDM2, and p53. TKIs blocked STAT5 nuclear entry, amplifying MDM2/p53 binding and subsequent p53 degradation. Additionally, STAT5 overexpression inhibited MDM2-mediated p53 ubiquitination, whereas knock-down of STAT5 destabilizes p53. Co-administration of MDM2 inhibitors stabilizes p53 ubiquitination induced by TKIs, enhancing pro-apoptotic effects on AML cells. Moreover, in mice engrafted with AML cells, gilteritinib treatment results in decreased p53 protein levels and the transcriptional repression of downstream genes in leukemia cells, which are mitigated by the co-administration of MDM2 inhibitors. In conclusion, our study shows that FLT3 TKIs impede STAT5 nuclear translocation, strengthening p53/MDM2 interaction and consequent p53 degradation. This finding reveals a novel mechanism of TKIs resistance and indicates a combination of MDM2 inhibitors with TKIs for AML therapy, offering new insights into effective treatment strategies.
FLT3突变存在于三分之一的急性髓系白血病（AML）患者中，是一个颇具吸引力的治疗靶点。尽管FLT3抑制剂显示出临床疗效，但由于多种机制，耐药性仍然是一个挑战。在本研究中，我们发现靶向FLT3的酪氨酸激酶抑制剂（TKIs）通过泛素化促使FLT3-ITD阳性AML细胞中的p53降解。STAT5磷酸化促进其核定位，导致STAT5、MDM2和p53之间的竞争性相互作用。TKIs阻断STAT5核进入，增强MDM2/p53结合及随后的p53降解。此外，STAT5过表达抑制MDM2介导的p53泛素化，而敲低STAT5会使p53不稳定。联合使用MDM2抑制剂可稳定TKIs诱导的p53泛素化，增强对AML细胞的促凋亡作用。此外，在植入AML细胞的小鼠中，吉列替尼治疗导致白血病细胞中p53蛋白水平降低和下游基因的转录抑制，而联合使用MDM2抑制剂可减轻这种情况。总之，我们的研究表明FLT3 TKIs阻碍STAT5核转位，增强p53/MDM2相互作用及随后的p53降解。这一发现揭示了TKIs耐药的新机制，并表明MDM2抑制剂与TKIs联合用于AML治疗，为有效治疗策略提供了新的见解。
