LOSS OF NEGATIVE SIGNALING BY THE G-CSFR IN AML

描述：（逐字改编自研究者摘要）尽管 在了解生长抑制因子方面已经取得了相当大的进展， 通过调节免疫反应的受体进行信号传导， 造血细胞因子介导"负"信号的机制 受体。最近，粒细胞集落刺激因子中的点突变 因子受体（G-CSFR）基因缺失的远端生长抑制结构域 G-CSFR已在急性髓细胞白血病（AML）患者中检测到， 其导致对G-CSF的超敏性和增强的细胞增殖。这些 在100%的AML患者中发现了突变， 先天性中性粒细胞减少症（SCN）。这些突变的普遍发生， SCN转化为AML的患者子集提供了强有力的证据， 它们会导致这部分患者的白血病转化。 来自G-CSFR的生长抑制信号的精确性质 在AML患者中被破坏的蛋白质仍是未知的。此外，角色 G-CSFR突变在无既往病史的AML患者中的发生率 SCN尚未得到充分研究。这里提出的实验更好地 了解G-CSFR调节负信号的机制， G-CSFR突变对白血病发生的作用。这些信息将 提供了对AML潜在病因机制的进一步了解， 为G-CSF的适当临床使用制定更好的定义指南 在急性粒细胞白血病患者中，并可能揭示新的治疗靶点 AML的治疗。

DESCRIPTION: (adapted verbatim from the investigator's abstract) Although considerable advances have been made in understanding growth inhibitory signaling by receptors that regulate immune responses, little is known about the mechanisms that mediate "negative" signaling by hematopoietic cytokine receptors. Recently, point mutations in the granulocyte colony-stimulating factor receptor (G-CSFR) gene deleting the distal growth inhibitory domain of the G-CSFR have been detected in patients with acute myelogenous leukemia (AML) that result in hypersensitivity to G-CSF and enhanced cell proliferation. These mutations have been identified in 100% of patients with AML preceded by server congenital neutropenia (SCN). The universal occurrence of these mutations in the subset of patients with SCN transforming to AML provides strong evidence that they contribute to leukemic transformation in this subset of patients. The precise nature of the growth inhibitory signals derived from the G-CSFR which are disrupted in patients with AML remain unknown. Additionally, the role of G-CSFR mutations in the development of AML in patients without antecedent SCN has not been adequately studied. Experiments are proposed here to better understand the mechanisms that regulate negative signaling by the G-CSFR and the contribution of G-CSFR mutations to leukemogenesis. This information will provide further insights into etiologic mechanisms underlying AML, permit the formulation of better defined guidelines for appropriate clinical use of G-CSF in patients with AML, and may reveal novel therapeutics targets for the treatment of AML.