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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 in 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.
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 cell survival, cell proliferation, and cell differentiation. However, its over-expression in blood cells (myeloid) is one of the main reasons for 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