FLT3 inhibition upregulates OCT4/NANOG to promote maintenance and TKI resistance of FLT3-ITD+ acute myeloid leukemia
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 ori...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-03-01
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| Series: | Oncogenesis |
| Online Access: | https://doi.org/10.1038/s41389-025-00553-6 |
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| author | Qi Zhou Zijian Li Pingping Zhao Yongyu Guan Huiyuan Chu Yaming Xi |
| author_facet | Qi Zhou Zijian Li Pingping Zhao Yongyu Guan Huiyuan Chu Yaming Xi |
| author_sort | Qi Zhou |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-054fd8d711c445db87689483128bb9c4 |
| institution | DOAJ |
| issn | 2157-9024 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Oncogenesis |
| spelling | doaj-art-054fd8d711c445db87689483128bb9c42025-08-20T02:48:57ZengNature Publishing GroupOncogenesis2157-90242025-03-0114111310.1038/s41389-025-00553-6FLT3 inhibition upregulates OCT4/NANOG to promote maintenance and TKI resistance of FLT3-ITD+ acute myeloid leukemiaQi Zhou0Zijian Li1Pingping Zhao2Yongyu Guan3Huiyuan Chu4Yaming Xi5The First Clinical Medical College of Lanzhou UniversityThe First Clinical Medical College of Lanzhou UniversityThe First Clinical Medical College of Lanzhou UniversityClinical laboratory, Gansu Provincial Maternal and Child Health Care HospitalSchool of Public Health, Gansu University of Traditional Chinese MedicineThe First Clinical Medical College of Lanzhou UniversityAbstract 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.https://doi.org/10.1038/s41389-025-00553-6 |
| spellingShingle | Qi Zhou Zijian Li Pingping Zhao Yongyu Guan Huiyuan Chu Yaming Xi FLT3 inhibition upregulates OCT4/NANOG to promote maintenance and TKI resistance of FLT3-ITD+ acute myeloid leukemia Oncogenesis |
| title | FLT3 inhibition upregulates OCT4/NANOG to promote maintenance and TKI resistance of FLT3-ITD+ acute myeloid leukemia |
| title_full | FLT3 inhibition upregulates OCT4/NANOG to promote maintenance and TKI resistance of FLT3-ITD+ acute myeloid leukemia |
| title_fullStr | FLT3 inhibition upregulates OCT4/NANOG to promote maintenance and TKI resistance of FLT3-ITD+ acute myeloid leukemia |
| title_full_unstemmed | FLT3 inhibition upregulates OCT4/NANOG to promote maintenance and TKI resistance of FLT3-ITD+ acute myeloid leukemia |
| title_short | FLT3 inhibition upregulates OCT4/NANOG to promote maintenance and TKI resistance of FLT3-ITD+ acute myeloid leukemia |
| title_sort | flt3 inhibition upregulates oct4 nanog to promote maintenance and tki resistance of flt3 itd acute myeloid leukemia |
| url | https://doi.org/10.1038/s41389-025-00553-6 |
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