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NOX4-driven ROS formation mediates PTP inactivation and cell transformation in FLT3ITD-positive AML cells.

A K Jayavelu1, J P Müller1, R Bauer1

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|August 27, 2015
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Activating mutations in FMS-like tyrosine kinase 3 (FLT3) drive acute myeloid leukemia (AML) by increasing reactive oxygen species (ROS) via NOX4, inactivating DEP-1. Targeting NOX4 may offer new AML therapies.

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Area of Science:

  • Hematology
  • Molecular Biology
  • Oncology

Background:

  • Activating mutations in FMS-like tyrosine kinase 3 (FLT3), particularly internal tandem duplications (ITDs), are linked to poor prognosis in acute myeloid leukemia (AML).
  • FLT3-ITD signaling promotes reactive oxygen species (ROS) production and inactivates the DEP-1 phosphatase, a key negative regulator of FLT3 signaling.

Purpose of the Study:

  • To elucidate the mechanisms by which FLT3-ITD signaling leads to ROS overproduction and DEP-1 inactivation.
  • To investigate the role of NADPH oxidase 4 (NOX4) in FLT3-ITD-driven transformation and its therapeutic potential in AML.

Main Methods:

  • Analysis of NOX4 expression in FLT3-ITD-positive cells.
  • Investigating the regulation of the NOX4 promoter by FLT3-ITD and STAT5.
  • Assessing the impact of NOX4 knockdown or knockout on ROS levels, DEP-1 activity, and cellular transformation.
  • Evaluating the efficacy of NOX4 inhibition in preclinical AML and myeloproliferative neoplasm (MPN) mouse models.

Main Results:

  • NOX4 expression was upregulated in FLT3-ITD-positive cells, dependent on FLT3-ITD signaling and STAT5.
  • NOX4 knockdown reduced ROS, restored DEP-1 activity, and attenuated FLT3-ITD-driven transformation.
  • Nox4 knockout cells were resistant to FLT3-ITD-mediated transformation.
  • NOX4 downregulation significantly reduced disease progression in mouse models of FLT3-ITD-driven myeloid malignancies.
  • NOX4-targeting compounds inhibited AML blast proliferation and MPN development in mice.

Conclusions:

  • FLT3-ITD signaling activates STAT5 to upregulate NOX4, leading to ROS overproduction, DEP-1 inactivation, and cellular transformation.
  • The FLT3-ITD-STAT5-NOX4 axis represents a novel mechanism in oncogenesis.
  • Targeting NOX4 offers a promising therapeutic strategy for a subset of AML patients with FLT3-ITD mutations.