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Internal tandem duplications in the gene encoding the membrane domain of FLT3 (FLT3-ITD) are the most common genetic alteration and an unfavorable prognostic factor in the patients with acute myeloid leukemia (AML). New-generation FLT3 inhibitors effectively induce cell death in the AML cells with the FLT3-ITD-positive phenotype (FLT3-ITD⁺) and potentially exhibit cytotoxic activity against the AML cells with the FLT3-ITD-negative phenotype (FLT3-ITD^-), but at higher concentrations. However, potential impact of the new-generation FLT3 inhibitors on the cytotoxic activity of molecular effectors of antitumor immunity - particularly in the context of heterogeneity of the primary clonal composition of AML, which includes both FLT3-ITD⁺ and FLT3-ITD^- cells - remains unclear. This study demonstrated that the use of quizartinib, a new-generation FLT3 inhibitor, increased resistance of the FLT3-ITD^- AML cells, but not of the FLT3-ITD⁺ AML cells, to the cytotoxic action of the key molecular effector of antitumor immunity, the cytokine Apo2L/TRAIL. This effect was mediated by the changes in the expression of proapoptotic TRAIL receptors, content of the cFLIP protein, and expression of the genes encoding proteins of the IAP and BCL-2 families. Additionally, the quizartinib-induced changes in the intracellular signaling pathways that potentially regulate TRAIL resistance in the AML cells were identified. The identified quizartinib-induced transcriptional changes are of interest not only in the context of combination therapy with TRAIL but also have broader implications for understanding the mechanisms of drug resistance in the AML cells.