MYELOID NEOPLASIA

kinase 3 (FLT3) is regulated by protein-tyrosine phosphatases (PTPs). We re-cently 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 inter-nal tandem duplication (ITD) protein. Our experiments revealed that DEP-1 was ex-pressed but dysfunctional in cells trans-formed 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 reacti-vated DEP-1. DEP-1 reactivation was also achieved by counteracting the high levels of reactive oxygen species (ROS) produc-tion detected in FLT3 ITD–expressing cell lines by inhibition of reduced NAD phos-phate (NADPH)–oxidases, or by overex-pression 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 man-ner, 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 transfor-mation by FLT3 ITD. (Blood. 2012;119(19): 4499-4511