G-CSFR MUTATIONS--A NOVEL MECHANISM OF LEUKEMOGENESIS

描述：（改编自研究者摘要）遗传性病变 涉及越来越多的癌基因已被确认发挥作用， 在人类白血病发展中的作用。 这些病变导致 基因正常功能的破坏或其不适当的 表情 大多数已经在急性胰腺炎中研究过的癌基因 骨髓性白血病（AML）编码的蛋白质， 细胞内信号分子或转录因子，并发挥作用， 在调节细胞增殖、分化和存活中的作用。 粒细胞集落刺激因子受体（G-CSFR）突变 最近报道了AML患者的基因，并提供了第一个 异常细胞因子受体与临床AML之间的联系。 这些突变 其导致G-CSFR的羧基末端区域的截短 破坏正常野生型G-CSFR的成熟信号功能， 导致对G-CSF过度增殖反应 机制 这种病变代表了白血病发生的一种新机制。 AML患者中G-CSFR基因突变的频率为 目前未知。 同样地，我们也不知道 促进显性阴性表型或信号通路， 介导增强的生长反应，以G-CSF的突变体G-CSFR形式从 AML患者。 这里提出实验以更好地理解 与G-CSFR的生长调节相关的信号传导事件和 G-CSFR基因突变导致不受调控的细胞增殖的机制 增殖 还将进行研究，以确定 AML患者中的G-CSFR突变。 这些信息将澄清 G-CSFR突变在AML发病机制中的作用， G-CSF在患者中适当临床使用的合理指南 与AML，并可能揭示潜在的新的治疗靶点， AML的治疗。

DESCRIPTION: (adapted from the investigator's abstract) Genetic lesions involving an increasing number of oncogenes have been recognized to play a role in the development of human leukemias. These lesions result in disruption of the normal function of genes or in their inappropriate expression. Most of the oncogenes which have been studied in acute myelogenous leukemia (AML) encode proteins that function either as intracellular signaling molecules or as transcription factors, and play a role in the regulation of cell proliferation, differentiation, and survival. Mutations of the granulocyte colony-stimulating factor receptor (G-CSFR) gene have recently been reported in patients with AML and provide the first link between abnormal cytokine receptors and clinical AML. These mutations which result in truncations of the carboxy-terminal region of the G-CSFR disrupt the maturation signaling function of the normal wild-type G-CSFR and lead to hyperproliferative responses to G-CSF through a dominant-negative mechanism. Such lesions represent a novel mechanism of leukemogenesis. The frequency of mutations in the G-CSFR gene in patients with AML is at present unknown. Likewise, little is known about the mechanisms that promote the dominant-negative phenotype or the signaling pathways that mediate enhanced growth responses to G-CSF by mutant G-CSFR forms from patients with AML. Experiments are proposed here to better understand the signaling events associated with growth regulation by the G-CSFR and the mechanisms by which mutations in the G-CSFR gene result in unregulated cell proliferation. Studies will also be done to determine the frequency of G-CSFR mutations in patients with AML. This information will clarify the role of G-CSFR mutations in the pathogenesis of AML, permit the formulation of rational guidelines for appropriate clinical use of G-CSF in patients with AML, and may reveal potential novel therapeutic targets for the treatment of AML.