NOX-driven ROS formation in cell transformation of FLT3-ITD-positive AML.
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 leukemias, causes activation of AKT and, subsequently, stabilization of p22phox, 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.
Institute of Molecular Cell Biology, CMB, Jena University Hospital, Jena, Germany.
Ashok Kumar
AK
Jayavelu
Tumour Biology Laboratory, School of Biochemistry and Cell Biology, Bioscience Research Institute, University College Cork, Cork, Ireland.
Jennifer N
JN
Moloney
Institute of Molecular Cell Biology, CMB, Jena University Hospital, Jena, Germany. Electronic address: boehmer@med.uni-jena.de.
Frank-D
FD
Böhmer
Tumour Biology Laboratory, School of Biochemistry and Cell Biology, Bioscience Research Institute, University College Cork, Cork, Ireland. Electronic address: t.cotter@ucc.ie.
Thomas G
TG
Cotter
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D004249:DNA Damage; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism*; D010084:Oxidation-Reduction; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D051941:fms-Like Tyrosine Kinase 3; D017027:Protein Tyrosine Phosphatases