RGS2 is an important target gene of Flt3-ITD mutations in AML and functions in myeloid differentiation and leukemic transformation
RGS2 is an important target gene of Flt3-ITD mutations in AML and functions in myeloid differentiation and leukemic transformation
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DOI：
10.1182/blood-2004-03-0940
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发表时间：
2005-03-01
期刊：
影响因子：
20.3
通讯作者：
Serve, H
中科院分区：
文献类型：
--
作者：
Schw채ble, J;Choudhary, C;Serve, H
激活胎肝酪氨酸激酶3（Flt 3）突变代表了急性髓细胞白血病（AML）中最常见的遗传畸变。最常见的是，它们作为在体外和体内转化骨髓细胞并诱导异常信号传导和生物学功能的质膜结构域（Flt 3-ITD）中的内部串联重复发生。我们确定了RGS 2，G蛋白信号的调节器，作为一个基因特异性抑制Flt 3-ITD。在这里，我们证明了RGS 2在Flt 3-ITD介导的转化中的重要作用。RGS 2在2个髓系细胞（32 Dcl 3和NB 4）中的激活Flt 3突变的强制表达后被抑制。此外，与Flt 3突变阴性病例相比，Flt 3突变阳性AML病例中RGS 2被抑制，特别是在具有高ITD与野生型（WT）比率的Flt 3-ITD阳性病例中。RGS 2与Flt 3-ITD共表达抑制Flt 3-ITD诱导的32 D细胞自主增殖和克隆生长。RGS 2还抑制Flt 3-ITD诱导的Akt和糖原合成酶激酶β（Gsk 3-β）磷酸化，而不影响信号转导子和转录激活子5（STAT 5）活化。此外，RGS 2再诱导Flt 3-ITD抑制的CCAAT/增强子结合蛋白α（c/EBPalpha）的表达，并拮抗Flt 3-ITD诱导的32 D细胞分化阻滞。在骨髓细胞系中的表达分析显示RGS 2在粒细胞分化过程中诱导，但在单核细胞分化过程中不诱导。总之，RGS 2是髓样分化的新介质，并且其抑制是Flt 3-ITD诱导的转化中的重要事件。(C)2005年美国血液学会。
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. (C) 2005 by The American Society of Hematology.