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

IF 5.9 2区 医学 Q1 ONCOLOGY
Qi Zhou, Zijian Li, Pingping Zhao, Yongyu Guan, Huiyuan Chu, Yaming Xi
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引用次数: 0

Abstract

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.

FLT3抑制上调OCT4/NANOG,促进FLT3- itd +急性髓系白血病的维持和TKI耐药。
高达30%的急性髓性白血病(AML)患者由于fms样受体酪氨酸激酶-3 (FLT3)内部串联重复(ITD)突变而面临不良结局。尽管FLT3抑制剂在治疗中显示出令人鼓舞的结果,但它们不能消除白血病干细胞,这是持续和耐药病变的起源。探索FLT3-ITD+ AML维持和化疗耐药的机制对于开发新的治疗方法至关重要。多能性转录因子(TFs)的表现及其与临床结果的联系已在各种肿瘤中得到证实。本研究探讨核心多能性TF与AML治疗之间的相关性。我们发现FLT3抑制可诱导FLT3- itd + AML细胞中OCT4和NANOG的上调。随后,我们证明了在FLT3-ITD+ AML细胞中,下调OCT4或NANOG抑制细胞生长,促进细胞凋亡,并诱导G0/G1细胞周期期阻滞。在小鼠肿瘤模型中,敲低OCT和NANOG抑制肿瘤生长。OCT4通过转录激活NANOG,增强异常FLT3信号通路,促进FLT3- itd + AML的恶性生物学行为。重要的是,OCT4或NANOG的下调增加了对flt3 -酪氨酸激酶抑制剂(TKI) (Gilteritinib)的反应性,这意味着OCT4和NANOG可能有助于FLT3-ITD+ AML的TKI耐药。我们的研究证实OCT4/NANOG参与调节TKI敏感性,靶向它们可能改善FLT3-TKIs在FLT3-ITD+ AML中的细胞毒性。
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来源期刊
Oncogenesis
Oncogenesis ONCOLOGY-
CiteScore
11.90
自引率
0.00%
发文量
70
审稿时长
26 weeks
期刊介绍: Oncogenesis is a peer-reviewed open access online journal that publishes full-length papers, reviews, and short communications exploring the molecular basis of cancer and related phenomena. It seeks to promote diverse and integrated areas of molecular biology, cell biology, oncology, and genetics.
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