Mutant FLT3 Causes DNA Damage Activating NADPH Oxidase

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(Last Updated On: October 21, 2017)
Formation of hydrogen peroxide catalyzed by NADPH oxidase

NADPH Oxidase complex catalyzes the formation or reactive oxygen species and hydrogen peroxide  Image source: Common Wikimedia

FMS-like Tyrosine Kinase 3 (FLT3) or fetal Liver Kinase 2 (Flk2) is a cytokine receptor belonging to the Receptor Tyrosine Kinase class 3 and is involved the expression of NADPH oxidase. Around 20% of the Acute Myeloid Leukemia (AML) patients have been found to have Internal Tandem Duplication of the FMS-like Tyrosine Kinase (FLT3-ITD) Receptor.

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Cells in which FLT3-ITD are expressed have been shown to generate high levels of Reactive Oxygen Species (ROS) and DNA Double Strand Breaks (DSBs). Signaling through FLT3 is necessary for the cell survival, cell proliferation and cell differentiation. However, its over-expression in blood cells (myeloid) is one of the main reasons of Acute Myeloid Leukemia.

According to the previous work of a team of researchers, inhibition of FLT3-ITD signaling causes post-translational down-regulation of P22phox. P22phox is a membrane-bound, a small subunit of the NADPH Oxidase (NOX) complex, which catalyzes the formation of Hydrogen Peroxide. The formation of these Reactive Oxygen Species causes DNA Double-Strand Breaks and is involved in the cancerous growth of the cells.



Researchers have now demonstrated that Myeloblast-like cell lines transfected with FLT3-ITD (32D) have higher levels of P22phox and P22phox interacting NOX isoforms than the cells (32D) transfected with the wild type of FLT3 receptors (FLT3-wt).

Inhibition of the NOX proteins and P22phox caused a decreased production of ROS. The level of the ORS was measured using a Hydrogen Peroxide specific dye, peroxy orange 1(PO1). However, nuclear Hydrogen Peroxide was measured using nuclear peroxy emerald 1 (NucPE1). These reductions in the level of Hydrogen Peroxide (ROS) were accompanied by a decrease in the number of DNA Double-Strand Breaks (DSBs).

They have also shown that 32D cells that express FLT3-ITD have a higher level of both oxidized DNA and Double Strand Breaks than their wild-type counterparts. They also found that NOX4 and P22phox localized to the nuclear membrane in the MV4-II cells expressing FLT3-ITD. In conclusion, these findings reveal that NOX and P22phox mediate the ROS production (mainly Hydrogen Peroxide) from the FLT3-ITD that signals to the nucleus and ultimately causes genomic instability.

Reference: Journal of Biological Chemistry

Article doi: 10.1074/jbc.M113.510495

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