RGS2 is an important target gene of Flt3-ITD mutations in AML and functions in myeloid differentiation and leukemic transformation.
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.
Schwäble
Joachim
J
Department of Medicine, Hematology, and Oncology, and the Interdisciplinary Clinical Research Center (IZKF), University Hospital Münster, Albert-Schweitzer-Strasse 33, 48129 Münster, Germany.
Choudhary
Chunaram
C
Thiede
Christian
C
Tickenbrock
Lara
L
Sargin
Bülent
B
Steur
Claudia
C
Rehage
Maike
M
Rudat
Annika
A
Brandts
Christian
C
Berdel
Wolfgang E
WE
Müller-Tidow
Carsten
C
Serve
Hubert
H
D000208:Acute Disease; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018922:HL-60 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology / Q000235:genetics*; D009154:Mutation; D022423:Myeloid Cells / Q000473:pathology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D020710:RGS Proteins / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012097:Repressor Proteins; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3
D011518:Proto-Oncogene Proteins; D020710:RGS Proteins; C087182:RGS2 protein, human; D012097:Repressor Proteins; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; C494918:AKT1 protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3