Format

Send to

Choose Destination
Leukemia. 2016 Feb;30(2):473-83. doi: 10.1038/leu.2015.234. Epub 2015 Aug 26.

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

Author information

1
Institute of Molecular Cell Biology, CMB, Jena University Hospital, Jena, Germany.
2
Division of Hematology and Hemostaseology and Ludwig Boltzmann Cluster Oncology, Department of Internal Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, Austria.
3
Ludwig Boltzmann Institute for Cancer Research, Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Veterinärplatz 1, Vienna, Austria, and Medical University of Vienna, Vienna, Austria.
4
Institut für Kardiovaskuläre Physiologie, Goethe-Universität Frankfurt, Sandhofstrasse 2, Frankfurt, Germany.
5
Cardiovascular Division, King's College London British Heart Foundation Centre, 125 Coldharbour Lane, London, UK.
6
Department of Hematology/Oncology, Jena University Hospital, Erlanger Allee 101, Jena, Germany.
7
Department of Medicine II, Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, Frankfurt, Germany.
8
German Cancer Consortium (DKTK), Heidelberg, Germany.
9
German Cancer Research Center (DKFZ), Heidelberg, Germany.
10
Clinic for Hematology and Oncology, University Hospital Magdeburg, Leipziger Str. 44, Magdeburg, Germany.

Abstract

Activating mutations of FMS-like tyrosine kinase 3 (FLT3), notably internal tandem duplications (ITDs), are associated with a grave prognosis in acute myeloid leukemia (AML). Transforming FLT3ITD signal transduction causes formation of reactive oxygen species (ROS) and inactivation of the protein-tyrosine phosphatase (PTP) DEP-1/PTPRJ, a negative regulator of FLT3 signaling. Here we addressed the underlying mechanisms and biological consequences. NADPH oxidase 4 (NOX4) messenger RNA and protein expression was found to be elevated in FLT3ITD-positive cells and to depend on FLT3ITD signaling and STAT5-mediated activation of the NOX4 promoter. NOX4 knockdown reduced ROS levels, restored DEP-1 PTP activity and attenuated FLT3ITD-driven transformation. Moreover, Nox4 knockout (Nox4(-/-)) murine hematopoietic progenitor cells were refractory to FLT3ITD-mediated transformation in vitro. Development of a myeloproliferative-like disease (MPD) caused by FLT3ITD-transformed 32D cells in C3H/HeJ mice, and of a leukemia-like disease in mice transplanted with MLL-AF9/ FLT3ITD-transformed murine hematopoietic stem cells were strongly attenuated by NOX4 downregulation. NOX4-targeting compounds were found to counteract proliferation of FLT3ITD-positive AML blasts and MPD development in mice. These findings reveal a previously unrecognized mechanism of oncoprotein-driven PTP oxidation, and suggest that interference with FLT3ITD-STAT5-NOX4-mediated overproduction of ROS and PTP inactivation may have therapeutic potential in a subset of AML.

PMID:
26308771
DOI:
10.1038/leu.2015.234
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center