NOX-driven ROS formation in cell transformation of FLT3-ITD-positive AML

被引:52
|
作者
Jayavelu, Ashok Kumar [1 ]
Moloney, Jennifer N. [2 ]
Boehmer, Frank-D. [1 ]
Cotter, Thomas G. [2 ]
机构
[1] Jena Univ Hosp, CMB, Inst Mol Cell Biol, Hans Knoll Str 2, D-07745 Jena, Germany
[2] Univ Coll Cork, Biosci Res Inst, Sch Biochem & Cell Biol, Tumour Biol Lab, Cork, Ireland
关键词
PROTEIN-TYROSINE PHOSPHATASES; ACUTE MYELOID-LEUKEMIA; INTERNAL TANDEM DUPLICATIONS; BCR-ABL; GENOMIC INSTABILITY; NADPH OXIDASES; DNA-DAMAGE; FLT3; ACTIVATION; MECHANISMS;
D O I
10.1016/j.exphem.2016.08.008
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
In different types of myeloid leukemia, increased formation of reactive oxygen species (ROS) has been noted and associated with aspects of cell transformation, including the promotion of leukemic cell proliferation and migration, as well as DNA damage and accumulation of mutations. Work reviewed in this article has revealed the involvement of NADPH oxidase (NOX)-derived ROS downstream of oncogenic protein tyrosine kinases in both processes, and the related pathways have been partially identified. FMS-like tyrosine kinase 3 with internal tandem duplications (FLT3-ITD), an important oncoprotein in a subset of acute myeloid leuke-mias, causes activation of AKT and, subsequently, stabilization of p22(phox), a regulatory subunit for NOX1-4. This process is linked to ROS formation and DNA damage. Moreover, FLT3-ITD signaling through STAT5 enhances expression of NOX4, ROS formation, and inactivation of the protein tyrosine phosphatase DEP-1/PTPRJ, a negative regulator of FLT3 signaling, by reversible oxidation of its catalytic cysteine residue. Genetic inactivation of NOX4 restores DEP-1 activity and attenuates cell transformation by FLT3-ITD in vitro and in vivo. Future work is required to further explore these mechanisms and their causal involvement in leukemic cell transformation, which may result in the identification of novel candidate targets for therapy. Copyright (C) 2016 ISEH-International Society for Experimental Hematology. Published by Elsevier Inc.
引用
收藏
页码:1113 / 1122
页数:10
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