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

Abstract:

: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.

journal_name

Exp Hematol

journal_title

Experimental hematology

authors

Jayavelu AK,Moloney JN,Böhmer FD,Cotter TG

doi

10.1016/j.exphem.2016.08.008

subject

Has Abstract

pub_date

2016-12-01 00:00:00

pages

1113-1122

issue

12

eissn

0301-472X

issn

1873-2399

pii

S0301-472X(16)30570-7

journal_volume

44

pub_type

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