Journal
LEUKEMIA
Volume 30, Issue 2, Pages 473-483Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2015.234
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Funding
- Deutsche Akademische Austauschdienst
- Deutsche Forschungsgemeinschaft [BO 1043/10, FI405/5-1, SFB815/TP1, SCHR1241/1-1, GRK 1715]
- German Jose-Carreras Leukemia Society [DJCLS SP12/08]
- Austrian Science Fund (FWF) SFB project [F4704, F4707]
- LOEWE Center for Cell and Gene Therapy by the German Cancer Consortium (DKTK)
- Fraunhofer Gesellschaft (graduate school translational research innovation pharma, TRIP)
- German Center for Cardiovascular Research (DZHK)
- British Heart Foundation [RG/13/11/30384] Funding Source: researchfish
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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.
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