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

- Oncogenic protein-tyrosine kinases, including FMS-like tyrosine kinase 3 with internal tandem-duplications (FLT3-ITD), act as drivers of reactive oxygen species (ROS) formation in myeloid leukemia.
- FLT3-ITD activates the pro-survival AKT pathway and subsequently stabilization of p22phox, a regulatory subunit of NADPH-oxidases (NOX) 1-4. Moreover, FLT3-ITD causes enhanced expression of NOX4 through activation of signal transducer and activator of transcription (STAT) 5, which binds directly to the NOX4 promoter.
- NOX4 driven ROS formation leads to inactivation of the protein-tyrosine phosphatase PTPRJ/DEP-1, thereby causally contributing to leukemic cell transformation.
- Furthermore, an increase in NOX-generated ROS is associated with an increase in DNA damage contributing to genetic instability and the accumulation of mutations associated with aggressive phenotypes, drug resistance and relapse.

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.