Blood Journal
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Cell transformation by FLT3 ITD in acute myeloid leukemia involves oxidative inactivation of the tumor suppressor protein-tyrosine phosphatase DEP-1/ PTPRJ

  1. Rinesh Godfrey1,
  2. Deepika Arora1,
  3. Reinhard Bauer1,2,
  4. Sabine Stopp1,
  5. Jörg P. Müller1,
  6. Theresa Heinrich1,
  7. Sylvia-Annette Böhmer1,
  8. Markus Dagnell3,
  9. Ulf Schnetzke4,
  10. Sebastian Scholl4,
  11. Arne Östman3, and
  12. Frank-D. Böhmer1
  1. 1Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany;
  2. 2Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany;
  3. 3Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden; and
  4. 4Department of Hematology/Oncology, Clinic for Internal Medicine II, Jena University Hospital, Jena, Germany


Signal transduction of FMS-like tyrosine kinase 3 (FLT3) is regulated by protein-tyrosine phosphatases (PTPs). We recently identified the PTP DEP-1/CD148/PTPRJ as a novel negative regulator of FLT3. This study addressed the role of DEP-1 for regulation of the acute myeloid leukemia (AML)–related mutant FLT3 internal tandem duplication (ITD) protein. Our experiments revealed that DEP-1 was expressed but dysfunctional in cells transformed by FLT3 ITD. This was caused by enzymatic inactivation of DEP-1 through oxidation of the DEP-1 catalytic cysteine. In intact cells, including primary AML cells, FLT3 ITD kinase inhibition reactivated DEP-1. DEP-1 reactivation was also achieved by counteracting the high levels of reactive oxygen species (ROS) production detected in FLT3 ITD–expressing cell lines by inhibition of reduced NAD phosphate (NADPH)–oxidases, or by overexpression of catalase or peroxiredoxin-1 (Prx-1). Interference with ROS production in 32D cells inhibited cell transformation by FLT3 ITD in a DEP-1–dependent manner, because RNAi-mediated depletion of DEP-1 partially abrogated the inhibitory effect of ROS quenching. Reactivation of DEP-1 by stable overexpression of Prx-1 extended survival of mice in the 32D cell/C3H/HeJ mouse model of FLT3 ITD–driven myeloproliferative disease. The study thus uncovered DEP-1 oxidation as a novel event contributing to cell transformation by FLT3 ITD.

  • Submitted February 11, 2011.
  • Accepted March 11, 2012.
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