文献类型：期刊文献

英文题名：FLT3 inhibition upregulates OCT4/NANOG to promote maintenance and TKI resistance of FLT3-ITD⁺ acute myeloid leukemia

作者：Zhou, Qi[1];Li, Zijian[1,2];Zhao, Pingping[1];Guan, Yongyu[3];Chu, Huiyuan[4];Xi, Yaming[1,2]

第一作者：Zhou, Qi

通信作者：Xi, YM[1];Xi, YM[2]

机构：[1]Lanzhou Univ, Clin Med Coll 1, Lanzhou, Peoples R China;[2]Lanzhou Univ, Hosp 1, Dept Hematol, Lanzhou, Peoples R China;[3]Gansu Prov Maternal & Child Hlth Care Hosp, Clin Lab, Lanzhou, Peoples R China;[4]Gansu Univ Tradit Chinese Med, Sch Publ Hlth, Lanzhou, Peoples R China

第一机构：Lanzhou Univ, Clin Med Coll 1, Lanzhou, Peoples R China

通信机构：[1]corresponding author), Lanzhou Univ, Clin Med Coll 1, Lanzhou, Peoples R China;[2]corresponding author), Lanzhou Univ, Hosp 1, Dept Hematol, Lanzhou, Peoples R China.

年份：2025

卷号：14

期号：1

外文期刊名：ONCOGENESIS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001454927700001)】；

语种：英文

摘要：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 crucial 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. 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. Knockdown of OCT and NANOG inhibited tumor growth in a mouse tumor model. OCT4 promotes the malignant biological behavior of FLT3-ITD+ AML by enhancing the abnormal FLT3 signaling pathway through transcriptional activation of NANOG. 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. Our study verifies the involvement of OCT4/NANOG in regulating TKI sensitivity and targeting them may improve the cytotoxicity of FLT3-TKIs in FLT3-ITD+ AML.