NF1 GENE IN MYELOID LEUKEMIA AND CYTOKINE SIGNALING

描述：(改编自调查员的摘要)处理 儿童骨髓增生异常综合征(MDS)以及慢性和急性 与Well相比，髓系白血病(CML和AML)仍然令人失望 儿童淋巴细胞性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 唐氏S综合征和1型神经纤维瘤病等异常 综合症。这些髓系疾病的遗传易感性表现为 研究特定基因产物在疾病中的作用的可能性 调节髓系细胞的生长和分化。初步证据 获得的结果表明NF1抑癌基因产物的丢失， 神经纤维蛋白使髓系细胞易发生白血病转化，在 部分是由于在生长后导致RAS活性增加和延长 因素刺激。这个项目将检验NF1的损失的假设 表达启动髓系白血病的发生是因为神经纤维素 通常会抑制髓系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)，可以 显著增加髓系细胞的数量。此外，这些信号 由GM-CSF受体激活的通路，对 NF1基因缺失对髓系细胞表型的影响有待鉴定。 这些目标将通过使用NF1基因缺陷、GM-CSF受体缺陷实现 小鼠和从这些小鼠衍生的永生化髓系细胞系。真知灼见 GMCSF信号通路失调性失控的机制探讨 神经纤维蛋白表达的研究可能有助于深入了解 骨髓增生性疾病和骨髓增生性疾病的过程。 这些洞察力将提出一些假设，这些假设将在一定程度上受到 针对其信号通路的治疗学研究进展 调节失调是该病表型的核心。因此，最终的目标是 这项提议是为了确定一种新的三环类的法尼基 抑制RAS蛋白功能的蛋白质转移酶(FPTase)抑制剂， 在几种MDS/髓系白血病小鼠模型中显示出治疗潜力 NF1基因突变。

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.