Decursin induces FLT3-ITD acute myeloid leukemia cell apoptosis by increasing the expression of the ubiquitin-conjugase UBE2L6.

Abstract

Mutation in the internal tandem duplication sequence of the FLT3 gene (FLT3-ITD) is linked to a poor clinical prognosis in acute myeloid leukemia (AML) patients. FLT3 inhibitors have demonstrated efficacy in improving the prognosis of AML patients with FLT3-ITD. However, the efficacy of FLT3 inhibitors is short-lived, and is often limited by secondary drug resistance when used alone. Recent investigations have provided an innovative approach for treating FLT3-ITD AML by targeting FLT3 protein degradation. Our study revealed that decursin selectively impaired the viability of FLT3-ITD-positive AML cells. Subsequent analysis revealed that decursin preferentially induced cell cycle arrest and apoptosis in FLT3-ITD-positive AML cells through proteasome-mediated FLT3-ITD degradation. Further research revealed that decursin significantly increased the expression of UBE2L6, an e2-conjugating enzyme that degrades FLT3-ITD. Downregulation of UBE2L6 by small hairpin RNA (shRNA) reduced decursin-induced FLT3-ITD-linked apoptosis and degradation. The anti-FLT3-ITD AML effect of decursin was also validated in cell lines and patient-derived mouse models. Moreover, decursin synergistically enhanced venetoclax-induced apoptosis.