12 month embargo at publisher's request. Restriction lift date: 2017-09-22
NOX-driven ROS formation in cell transformation of FLT3-ITD positive AML
Jayavelu, Ashok K.
Moloney, Jennifer N.
Böhmer, Frank D.
Cotter, Thomas G.
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 shown 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. FLT3-ITD, an important oncoprotein in a subset of AML, 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 restored DEP-1 activity and attenuated 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.
PTP oxidation , Protein-tyrosine phosphatase (PTP) , DNA damage , FLT3-ITD , AML , Reactive oxygen species , Myeloid leukemia
Jayavelu, A. K., Moloney, J. N., Böhmer, F.-D. and Cotter, T. G. (2016) ‘NOX-driven ROS formation in cell transformation of FLT3-ITD positive AML’, Experimental Hematology, 44(12), pp. 1113-1122. doi: 10.1016/j.exphem.2016.08.008