LncRNA LFQR promotes cytoactivity and resistance to quizartinib via FLT3 transcriptional activation in FLT3-ITD acute myeloid leukemia

FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) acute myeloid leukemia (AML) is an adverse subtype of leukemia associated with a poor patient prognosis. FLT3 inhibitors exhibit promising clinical activity, however, their effectiveness is limited by drug resistance. Therefore, overcoming resistance to FLT3 inhibitors remains an important clinical problem, necessitating the development of new strategies. In this study, we identified a lncRNA, AL713998.1, which was upregulated in both FLT3-ITD AML and quizartinib-resistant cells (LFQR). In vitro experiments showed that LFQR silencing significantly inhibited cell proliferation, impaired self-renewal capacity, caused cell cycle arrest and induced cell differentiation, specifically in FLT3-ITD AML. In addition, the interaction of LFQR with SFPQ was verified using RNA pull-down assays, mass spectrometry and RNA immunoprecipitation. Mechanistically, LFQR promotes SFPQ binding to the promoter region of FLT3 and facilitates transcriptional regulation, thereby increasing the expression of kinase and oncoproteins in FLT3-ITD AML cells. Notably, LFQR inhibition also impaired the cytoactivity of quizartinib cells and reversed their resistance to quizartinib. Overall, our study highlights that LFQR may serve as a potential therapeutic target in FLT3-ITD AML, and its knockdown can significantly improve the efficacy of quizartinib, thus providing a promising strategy for overcoming resistance to FLT3 inhibitors.