NF1 GENE IN MYELOID LEUKEMIA AND CYTOKINE SIGNALING

髓系白血病中的 NF1 基因和细胞因子信号转导

• 批准号: 6376796
• 负责人: DAVID ANDREW LARGAESPADA
• 金额: $ 9.73万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6376796
• 关键词: SDS polyacrylamide gel electrophoresis; apoptosis; biological signal transduction; cell line; colony stimulating factor; cytokine; flow cytometry; gene expression; growth factor receptors; laboratory mouse; myelogenous leukemia; myeloid stem cell; neoplastic transformation; neurofibromatosis; tissue /cell culture; tumor suppressor proteins

DESCRIPTION: (adapted from the investigator's abstract) Treatment of childhood myelodysplastic syndromes (MDS) as well as chronic and acute myeloid leukemia (CML and AML) remains disappointing compared with well known advances in the treatment of childhood lymphoblastic leukemia. Childhood MDS, CML, and AML are often associated with constitutional genetic abnormalities, such as Down s syndrome and Neurofibromatosis type 1 (NF1) syndrome. Inherited predisposition to these myeloid diseases presents the possibility of investigation into the role of specific gene products in regulating myeloid cell growth and differentiation. Preliminary evidence obtained suggests that loss of the NF1 tumor suppressor gene product, neurofibromin, predisposes myeloid cells to leukemic transformation, in part, by causing increased and prolonged Ras activation following growth factor stimulation. This project will test the hypothesis that loss of NF1 expression initiates myeloid leukemia development because neurofibromin normally represses the response of myeloid cells to a cytokine, granulocyte/macrophage-colony stimulating factor (GM-CSF), that can dramatically increase myeloid cell numbers. Furthermore, those signaling pathways, activated by the GM-CSF receptor, which are most important for the phenotypic effects of NF1 gene loss on myeloid cells with be identified. These goals will be met using Nf1 gene-deficient, GM-CSF receptor-deficient mice and immortalized myeloid cell lines derived from these mice. Insights into the mechanisms of deregulation of the GM-CSF signaling pathway by loss of neurofibromin expression is likely to lend insight into fundamental processes of myelodysplastic and myeloproliferative hematopoietic disorders. These insights will suggest hypotheses that will, in part, be tested by the development of therapeutics which target those signaling pathways whose dysregulation is central to the disease phenotype. Thus, a final goal of this proposal is to determine if a novel, tricyclic class of the farnesyl protein transferase (FPTase) inhibitors, which inhibit Ras protein function, show therapeutic potential in several mouse models of MDS/myeloid leukemia with Nf1 gene mutation.

描述：（改编自研究者的摘要） 儿童骨髓增生异常综合征 (MDS) 以及慢性和急性 与健康状况相比，粒细胞白血病（CML 和 AML）仍然令人失望 儿童淋巴细胞白血病治疗的已知进展。 儿童 MDS、CML 和 AML 通常与体质遗传有关 异常，例如唐氏综合症和 1 型神经纤维瘤病 (NF1) 综合症。 这些骨髓疾病的遗传倾向表明 研究特定基因产物的作用的可能性 调节骨髓细胞的生长和分化。 初步证据 获得的结果表明 NF1 肿瘤抑制基因产物的丢失， 神经纤维蛋白，使骨髓细胞易于白血病转化， 部分是通过在生长后引起 Ras 激活增加和延长 因子刺激。 该项目将测试 NF1 缺失的假设 表达启动骨髓性白血病的发展，因为神经纤维蛋白 通常抑制骨髓细胞对细胞因子的反应， 粒细胞/巨噬细胞集落刺激因子 (GM-CSF) 显着增加骨髓细胞数量。 此外，那些信号 GM-CSF 受体激活的途径，对于 NF1 基因缺失对骨髓细胞的表型影响尚待确定。 这些目标将通过使用 Nf1 基因缺陷、GM-CSF 受体缺陷来实现 小鼠和源自这些小鼠的永生化骨髓细胞系。 见解 探究 GM-CSF 信号通路因丢失而失调的机制 神经纤维蛋白表达的研究可能有助于深入了解神经纤维蛋白的基本原理 骨髓增生异常和骨髓增生性造血障碍的过程。 这些见解将提出一些假设，这些假设将在一定程度上由 开发针对那些信号通路的治疗方法 失调是疾病表型的核心。 因此，最终目标是 该提案旨在确定是否有一种新颖的三环类法尼基 蛋白转移酶（FPTase）抑制剂，抑制 Ras 蛋白功能， 在几种 MDS/骨髓性白血病小鼠模型中显示出治疗潜力 带有Nf1基因突变。