FLT3 inhibitors induce p53 instability, driven by STAT5/MDM2/p53 competitive interactions in acute myeloid leukemia

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.