NADPH oxidase mediated oxidative stress signaling in FLT3-ITD acute myeloid leukemia
Abstract The internal tandem duplication of the juxtamembrane domain of the FMS-like tyrosine kinase 3 (FLT3-ITD) is the most common genetic change in acute myeloid leukemia (AML), and about 30% of all AMLs harbor a FLT3-ITD mutation. Even though FLT3 inhibitors have displayed encouraging effects in...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-06-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01528-5 |
| _version_ | 1827911000248025088 |
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| author | Yongfeng Chen Zhenyou Zou Mihnea-Alexandru Găman Linglong Xu Jing Li |
| author_facet | Yongfeng Chen Zhenyou Zou Mihnea-Alexandru Găman Linglong Xu Jing Li |
| author_sort | Yongfeng Chen |
| collection | DOAJ |
| description | Abstract The internal tandem duplication of the juxtamembrane domain of the FMS-like tyrosine kinase 3 (FLT3-ITD) is the most common genetic change in acute myeloid leukemia (AML), and about 30% of all AMLs harbor a FLT3-ITD mutation. Even though FLT3 inhibitors have displayed encouraging effects in FLT3-ITD-mutated AML, the extent of the clinical response to these compounds is cut short due to the rapid development of drug resistance. Evidence has shown that FLT3-ITD triggered activation of oxidative stress signaling may exert a pivotal role in drug resistance. The downstream pathways of FLT3-ITD, including STAT5, PI3K/AKT, and RAS/MAPK, are considered to be major oxidative stress signaling pathways. These downstream pathways can inhibit apoptosis and promote proliferation and survival by regulating apoptosis-related genes and promoting the generation of reactive oxygen species (ROS) through NADPH oxidase (NOX) or other mechanisms. Appropriate levels of ROS may promote proliferation, but high levels of ROS can lead to oxidative damage to the DNA and increase genomic instability. In addition, post-translational modifications of FLT3-ITD and changes in its subcellular localization can affect downstream signaling which may also be one of the mechanisms leading to drug resistance. In this review, we summarized the research progress on NOX mediated oxidative stress signaling and its relationship with drug resistance in FLT3-ITD AML, and discuss the possible new targets in FLT3-ITD signal blocking to reverse drug resistance in FLT3-ITD-mutated AML. |
| first_indexed | 2024-03-13T01:57:13Z |
| format | Article |
| id | doaj.art-35870d8fd8494864b7503619ae1cda8d |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-03-13T01:57:13Z |
| publishDate | 2023-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-35870d8fd8494864b7503619ae1cda8d2023-07-02T11:07:13ZengNature Publishing GroupCell Death Discovery2058-77162023-06-01911810.1038/s41420-023-01528-5NADPH oxidase mediated oxidative stress signaling in FLT3-ITD acute myeloid leukemiaYongfeng Chen0Zhenyou Zou1Mihnea-Alexandru Găman2Linglong Xu3Jing Li4Department of Basic Medical Sciences, Medical College of Taizhou UniversityInstitute of Psychosis Prevention, Brain Hospital of Guangxi Zhuang Autonomous RegionFaculty of Medicine, “Carol Davila” University of Medicine and PharmacyDepartment of Hematology, Taizhou Central Hospital (Taizhou University Hospital)Department of Histology and Embryology, North Sichuan Medical CollegeAbstract The internal tandem duplication of the juxtamembrane domain of the FMS-like tyrosine kinase 3 (FLT3-ITD) is the most common genetic change in acute myeloid leukemia (AML), and about 30% of all AMLs harbor a FLT3-ITD mutation. Even though FLT3 inhibitors have displayed encouraging effects in FLT3-ITD-mutated AML, the extent of the clinical response to these compounds is cut short due to the rapid development of drug resistance. Evidence has shown that FLT3-ITD triggered activation of oxidative stress signaling may exert a pivotal role in drug resistance. The downstream pathways of FLT3-ITD, including STAT5, PI3K/AKT, and RAS/MAPK, are considered to be major oxidative stress signaling pathways. These downstream pathways can inhibit apoptosis and promote proliferation and survival by regulating apoptosis-related genes and promoting the generation of reactive oxygen species (ROS) through NADPH oxidase (NOX) or other mechanisms. Appropriate levels of ROS may promote proliferation, but high levels of ROS can lead to oxidative damage to the DNA and increase genomic instability. In addition, post-translational modifications of FLT3-ITD and changes in its subcellular localization can affect downstream signaling which may also be one of the mechanisms leading to drug resistance. In this review, we summarized the research progress on NOX mediated oxidative stress signaling and its relationship with drug resistance in FLT3-ITD AML, and discuss the possible new targets in FLT3-ITD signal blocking to reverse drug resistance in FLT3-ITD-mutated AML.https://doi.org/10.1038/s41420-023-01528-5 |
| spellingShingle | Yongfeng Chen Zhenyou Zou Mihnea-Alexandru Găman Linglong Xu Jing Li NADPH oxidase mediated oxidative stress signaling in FLT3-ITD acute myeloid leukemia Cell Death Discovery |
| title | NADPH oxidase mediated oxidative stress signaling in FLT3-ITD acute myeloid leukemia |
| title_full | NADPH oxidase mediated oxidative stress signaling in FLT3-ITD acute myeloid leukemia |
| title_fullStr | NADPH oxidase mediated oxidative stress signaling in FLT3-ITD acute myeloid leukemia |
| title_full_unstemmed | NADPH oxidase mediated oxidative stress signaling in FLT3-ITD acute myeloid leukemia |
| title_short | NADPH oxidase mediated oxidative stress signaling in FLT3-ITD acute myeloid leukemia |
| title_sort | nadph oxidase mediated oxidative stress signaling in flt3 itd acute myeloid leukemia |
| url | https://doi.org/10.1038/s41420-023-01528-5 |
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