CircTADA2A stabilizes p53 via interacting with TRIM28 and suppresses the maintenance of FLT3-ITD acute myeloid leukemia

Abstract

Internal tandem duplication mutations in the FMS-like tyrosine kinase 3 (FLT3-ITDs) occur in 25%–30% of acute myeloid leukemia (AML) cases and are associated with adverse prognosis. RNA-based therapeutics exhibit significant potential for treating diseases, prompting us to develop a novel circular RNA (circRNA)-based therapeutic strategy for FLT3-ITD AML. Here, we find circTADA2A is downregulated in FLT3-ITD AML patients. We further demonstrate that the downregulation of circTADA2A is critical for the proliferation of human FLT3-ITD AML cells, the sustenance of AML, and the self-renewal of leukemia stem/initiating cells (LSCs/LICs). Mechanistically, circTADA2A inhibits the TRIM28/MDM2 complexes formation by competitively binding to TRIM28, resulting in decreased levels of p53 ubiquitination and activating the p53 pathway. Importantly, in vitro transcription of circTADA2A and in vivo delivery via lipid nanoparticles (LNPs) significantly enhance the elimination of FLT3-ITD leukemia cells in combination with quizartinib treatment. In conclusion, our work uncovers the crucial functions of circTADA2A in the maintenance of FLT3-ITD AML and highlights a translationally important circTADA2A-based therapeutic approach for FLT3-ITD AML treatment.