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

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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.

authors

  • Jayavelu, AK
  • Müller, JP
  • Bauer, R
  • Böhmer, S-A
  • Lässig, J
  • Cerny-Reiterer, S
  • Sperr, WR
  • Valent, P
  • Maurer, B
  • Moriggl, R
  • Schröder, K
  • Shah, AM
  • Fischer, M
  • Scholl, S
  • Barth, J
  • Oellerich, T
  • Berg, Tobias
  • Serve, H
  • Frey, S
  • Fischer, T
  • Heidel, FH
  • Böhmer, F-D

publication date

  • February 2016

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