LOSS OF NEGATIVE SIGNALING BY THE GCSFR IN AML

描述：（从研究者的摘要逐字改编）尽管

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.