title: Cell transformation by FLT3 ITD in acute myeloid leukemia involves oxidative inactivation of the tumor suppressor protein-tyrosine phosphatase DEP-1/ PTPRJ.
abstract: 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.
authors.affiliation: Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany.
authors.forename: Rinesh
authors.initials: R
authors.lastname: Godfrey
authors.forename: Deepika
authors.initials: D
authors.lastname: Arora
authors.forename: Reinhard
authors.initials: R
authors.lastname: Bauer
authors.forename: Sabine
authors.initials: S
authors.lastname: Stopp
authors.forename: Jörg P
authors.initials: JP
authors.lastname: Müller
authors.forename: Theresa
authors.initials: T
authors.lastname: Heinrich
authors.forename: Sylvia-Annette
authors.initials: SA
authors.lastname: Böhmer
authors.forename: Markus
authors.initials: M
authors.lastname: Dagnell
authors.forename: Ulf
authors.initials: U
authors.lastname: Schnetzke
authors.forename: Sebastian
authors.initials: S
authors.lastname: Scholl
authors.forename: Arne
authors.initials: A
authors.lastname: Östman
authors.forename: Frank-D
authors.initials: FD
authors.lastname: Böhmer
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016147:Genes, Tumor Suppressor / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000494:pharmacology; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020080:Tandem Repeat Sequences / Q000235:genetics; D014162:Transfection; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D016877:Oxidants; D017382:Reactive Oxygen Species; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C486288:PTPRJ protein, human; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3