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Mechanisms of resistance

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

Leukemia volume 30, pages 473–483 (2016)Cite this article

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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.

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Acknowledgements

We thank Drs Jack Arbiser, Carmen Döbele, Adrian Manea, Siavosh Mahboobi, Frank Schnütgen and Maya Simionescu for the kind provision of reagents. We are grateful for support by the Deutsche Akademische Austauschdienst (to AKJ), by the Deutsche Forschungsgemeinschaft to F-DB (BO 1043/10), TF and FHH (FI405/5-1), to KS (SFB815/TP1 and SCHR1241/1-1), and to AKJ (associated member of GRK 1715), by the German Jose-Carreras Leukemia Society (DJCLS SP12/08) to FHH, by the Austrian Science Fund (FWF) SFB project F4704 and F4707 to RM and PV, by the LOEWE Center for Cell and Gene Therapy by the German Cancer Consortium (DKTK) to TB and TO, the Fraunhofer Gesellschaft (graduate school translational research innovation pharma, TRIP) to KS, and the German Center for Cardiovascular Research (DZHK) to KS.

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Authors and Affiliations

  1. Institute of Molecular Cell Biology, CMB, Jena University Hospital, Jena, Germany

    A K Jayavelu, J P Müller, R Bauer, S-A Böhmer, J Lässig & F-D Böhmer

  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

    S Cerny-Reiterer, W R Sperr & P Valent

  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

    B Maurer & R Moriggl

  4. Institut für Kardiovaskuläre Physiologie, Goethe-Universität Frankfurt, Sandhofstrasse 2, Frankfurt, Germany,

    K Schröder

  5. Cardiovascular Division, King’s College London British Heart Foundation Centre, 125 Coldharbour Lane, London, UK,

    A M Shah

  6. Department of Hematology/Oncology, Jena University Hospital, Erlanger Allee 101, Jena, Germany,

    M Fischer & S Scholl

  7. Department of Medicine II, Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, Frankfurt, Germany,

    J Barth, T Oellerich, T Berg & H Serve

  8. German Cancer Consortium (DKTK), Heidelberg, Germany

    J Barth

  9. German Cancer Research Center (DKFZ), Heidelberg, Germany

    J Barth

  10. Clinic for Hematology and Oncology, University Hospital Magdeburg, Leipziger Str. 44, Magdeburg, Germany,

    S Frey, T Fischer & F H Heidel

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Jayavelu, A., Müller, J., Bauer, R. et al. NOX4-driven ROS formation mediates PTP inactivation and cell transformation in FLT3ITD-positive AML cells. Leukemia 30, 473–483 (2016). https://doi.org/10.1038/leu.2015.234

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