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RGS2 is an important target gene of Flt3-ITD mutations in AML and functions in myeloid differentiation and leukemic transformation.

Schwäble J, Choudhary C, Thiede C, Tickenbrock L, Sargin B, Steur C, Rehage M, Rudat A, Brandts C, Berdel WE, Müller-Tidow C, Serve H

Department of Medicine, Hematology, and Oncology, and the Interdisciplinary Clinical Research Center (IZKF), University Hospital Münster, Albert-Schweitzer-Strasse 33, 48129 Münster, Germany.

Activating fetal liver tyrosine kinase 3 (Flt3) mutations represent the most common genetic aberrations in acute myeloid leukemia (AML). Most commonly, they occur as internal tandem duplications in the juxtamembrane domain (Flt3-ITD) that transform myeloid cells in vitro and in vivo and that induce aberrant signaling and biologic functions. We identified RGS2, a regulator of G-protein signaling, as a gene specifically repressed by Flt3-ITD. Here we demonstrate an important role of RGS2 in Flt3-ITD-mediated transformation. RGS2 was repressed after forced expression of activating Flt3 mutations in 2 myeloid cell lines (32Dcl3 and NB4). Furthermore, RGS2 was repressed in Flt3-mutation-positive AML cases in comparison to Flt3-mutation-negative cases, especially in Flt3-ITD-positive cases with a high ITD-to-wild-type (WT) ratio. Coexpression of RGS2 with Flt3-ITD inhibited Flt3-ITD-induced autonomous proliferation and clonal growth of 32D cells. RGS2 also inhibited Flt3-ITD-induced phosphorylation of Akt and glycogen synthase kinase beta (Gsk3-beta) without influencing signal transducer and activator of transcription 5 (STAT5) activation. In addition, RGS2 reinduced the expression of Flt3-ITD-repressed CCAAT/enhancer-binding protein alpha (c/EBPalpha) and antagonized the Flt3-ITD-induced differentiation block in 32D cells. Expression analyses in myeloid cell lines revealed induction of RGS2 during granulocytic but not during monocytic differentiation. Taken together, RGS2 is a novel mediator of myeloid differentiation, and its repression is an important event in Flt3-ITD-induced transformation.

Published 17 February 2005 in Blood, 105(5): 2107-14.
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