TRIM22-mediated ubiquitin-dependent degradation of FLT3-ITD overcomes TKI resistance in acute myeloid leukemia.

Abstract

FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations, found in 25%-30% of acute myeloid leukemia (AML) patients, cause poor prognosis and resistance to FLT3 tyrosine kinase inhibitors (TKIs). We show that APG-115 selectively kills FLT3-ITD cells by activating p53. This critically upregulates TRIM22 (Tripartite motif-containing protein 22), an essential E3 ubiquitin ligase that directly binds FLT3-ITD, promotes its polyubiquitination, and induces its proteasomal degradation. This TRIM22-mediated mechanism offers a novel strategy to overcome intrinsic and acquired TKI resistance. Unlike inhibitors such as AC220, which suppress FLT3 signaling but downregulate p53, APG-115 restores p53 function and induces TRIM22, enabling potent synergy with FLT3 inhibitors. TRIM22 is essential for APG-115's suppression of leukemia stem cells, inducing cell cycle arrest, myeloid differentiation, and reduced clonogenic potential. The combination of APG-115 and AC220 significantly enhances apoptosis in FLT3-ITD AML models and primary cells, while sparing normal cells. It shows robust efficacy in preclinical xenograft models, reducing tumor burden and extending survival. This work establishes targeting the p53/TRIM22 axis, reliant on TRIM22's unique activity against FLT3-ITD, as a highly promising therapeutic approach for FLT3-ITD AML, including resistant disease.