G-CSFR MUTATIONS--A NOVEL MECHANISM OF LEUKEMOGENESIS

G-CSFR突变——白血病发生的新机制

• 批准号: 2382809
• 负责人: Belinda Rene Avalos
• 金额: $ 14.6万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2382809
• 关键词: acute myelogenous leukemia; carcinogenesis; clinical research; colony stimulating factor; enzyme activity; gene mutation; growth factor receptors; guanine nucleotide binding protein; human genetic material tag; human subject; mitogen activated protein kinase; neoplasm /cancer genetics; phosphatidylinositol 3 kinase; polymerase chain reaction

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.

描述：（改编自研究者的摘要）遗传病变 涉及越来越多的癌基因已被认为发挥着 在人类白血病的发展中发挥作用。 这些病变导致 破坏基因的正常功能或使其不适当 表达。 大多数已在急性研究中研究过的癌基因 骨髓性白血病 (AML) 编码的蛋白质具有以下功能： 细胞内信号分子或作为转录因子，并发挥 在细胞增殖、分化和存活的调节中发挥作用。 粒细胞集落刺激因子受体 (G-CSFR) 突变 最近在 AML 患者中报道了该基因，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 这导致 G-CSFR 的羧基末端区域被截断 破坏正常野生型 G-CSFR 的成熟信号功能， 通过显性失活导致对 G-CSF 的过度增殖反应 机制。 这种病变代表了一种新的白血病发生机制。 AML 患者 G-CSFR 基因突变频率为 目前未知。 同样，人们对于其机制知之甚少。 促进显性失活表型或信号通路 通过突变的 G-CSFR 形式介导对 G-CSF 的增强生长反应 患有 AML 的患者。 这里提出实验是为了更好地理解 与 G-CSFR 和 G-CSFR 基因突变导致细胞不受调控的机制 增殖。 还将进行研究以确定发生频率 AML 患者的 G-CSFR 突变。 此信息将澄清 G-CSFR 突变在 AML 发病机制中的作用，允许制定 患者临床上适当使用 G-CSF 的合理指南 与 AML 相关，并可能揭示潜在的新治疗靶点 AML 的治疗。