FLT3 inhibition upregulates OCT4/NANOG to promote proliferation and TKI resistance of FLT3-ITD+ acute myeloid leukemia

Abstract Background: Up to 30% of acute myeloid leukemia (AML) patients face unfavorable outcomes due to the FMS-like receptor tyrosine kinase-3 (FLT3) internal tandem duplication (ITD) mutation. Although FLT3 inhibitors show encouraging outcomes in treatment, they fail to eliminate leukemia stem cells, the origin of persistent and resistant lesions. Exploration of the mechanism in FLT3-ITD+ AML maintenance and chemoresistance is crutial for the development of novel therapeutic approaches. The manifestation of pluripotency transcription factors (TFs) and their link to clinical outcomes have been documented in various tumors. This study investigates the correlation between core pluripotency TF and treatment in AML. Results: We discovered that FLT3 inhibition induced upregulation of OCT4 and NANOG in FLT3-ITD+ AML cells. Subsequently, we demonstrated that downregulation of OCT4 or NANOG inhibited cell growth, promoted apoptosis, and induced G0/G1 cell cycle phase arrest in FLT3-ITD+ AML cells. Importantly, downregulation of OCT4 or NANOG increased responsiveness to FLT3-tyrosine kinase inhibitor (TKI) (gilteritinib), implying that OCT4 and NANOG may contribute to TKI resistance in FLT3-ITD+AML. Conclusion: Our study verifies the involvement of OCT4 and NANOG in regulating TKI sensitivity, and targeting them may improve the cytotoxicity of FLT3 TKIs in FLT3-ITD+ AML.