NADPH oxidase mediated oxidative stress signaling in FLT3-ITD acute myeloid leukemia
Yongfeng Chen1, Zhenyou Zou2, Mihnea-Alexandru Găman3,4
1Department of Basic Medical Sciences, Medical College of Taizhou University, Taizhou, Zhejiang, 318000, China. cyfeng@tzc.edu.cn.
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.
Insights
FLT3-ITD mutations drive acute myeloid leukemia (AML) drug resistance via oxidative stress pathways. Targeting NADPH oxidase (NOX) mediated signaling may overcome resistance in FLT3-ITD AML.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- FLT3-ITD mutations are common in acute myeloid leukemia (AML), conferring poor prognosis.
- FLT3 inhibitors show efficacy but are limited by rapid drug resistance.
- Oxidative stress signaling, particularly via NADPH oxidase (NOX), is implicated in FLT3-ITD-mediated drug resistance.
Purpose of the Study:
- To review the role of NOX-mediated oxidative stress in FLT3-ITD AML drug resistance.
- To discuss potential therapeutic strategies targeting oxidative stress pathways to overcome resistance.
Main Methods:
- Literature review of studies on FLT3-ITD, oxidative stress, and drug resistance in AML.
- Analysis of downstream signaling pathways (STAT5, PI3K/AKT, RAS/MAPK) in FLT3-ITD AML.
- Examination of the role of reactive oxygen species (ROS) and NOX in drug resistance.
Main Results:
- FLT3-ITD activates oxidative stress pathways, promoting proliferation and inhibiting apoptosis.
- Elevated ROS levels contribute to DNA damage and genomic instability.
- Post-translational modifications and altered subcellular localization of FLT3-ITD can influence signaling and resistance.
Conclusions:
- NOX-mediated oxidative stress is a key mechanism of drug resistance in FLT3-ITD AML.
- Targeting NOX and related oxidative stress pathways presents a promising strategy to reverse drug resistance.
- Further research into FLT3-ITD signaling and oxidative stress is crucial for developing novel AML therapies.
