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

Abstract Activating 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 two myeloid cell lines (32Dcl3 and NB4). Furthermore, RGS-2 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 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 Gsk3-beta without influencing STAT5 activation. In addition, RGS2 re-induced the expression of Flt3-ITD-repressed 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.From bloodjournal.hematologylibrary.org by guest on June 7, 2013. For personal use only.