CHILDHOOD CANCER GENE PROGRAM PROJECT

该计划项目的长期目标是提高对 儿童癌症的发病机制和病理生理学以及 利用在实验室中获得的分子洞察力来设计新的 评估预后和改善治疗的手段。这个宏大的目标 正在通过五个协调的项目进行，这些项目得到了 管理、转基因、分子细胞遗传学和分子 诊断核心。在项目1(M.Roussel)中，目标是澄清 CDK4/CDK6细胞周期蛋白D依赖性激酶的INK4抑制剂在心肌梗死中的作用 儿童癌症的起源。INK4家族的每个已知成员 阻止细胞通过第一个间隙(细胞的G1期 细胞周期，但它们对肿瘤发生的贡献仍有待于 已定义。项目2(S.Baker)将讨论EWS-ETS的作用 嵌合转录因子家族在异常生长和发育中的作用 尤文氏肉瘤的鉴别诊断EWS相互作用蛋白将是 经鉴定的、易通过融合转化的细胞类型 蛋白质将在转基因小鼠中被定义。的工作假说 项目3(J.Downing)是AML1融合蛋白有助于 通过干扰通常由基因调控的靶基因导致白血病 AML1/CBFβ复合体。这个角色将通过定义正常 AML1基因在胚胎和造血细胞中的功能 发展。项目4(D.夏皮罗)的目的是确定 PAX3-FKHR癌蛋白通过不同的机制 转化成肌源性细胞，导致泡状横纹肌肉瘤。小说 已经开发了体外模型来评估强制实施的效果 Pax3-FKHR在肌源性分化中的表达。项目5(A.T.Look) 将依靠荧光原位杂交等分子 识别和表征推定的属性的方法 染色体1p上的神经母细胞瘤抑制基因。这项为期5年的计划 寻求将领先的分子生物学家的努力与 全面的核心服务，回答有关 导致儿童肿瘤的机制。它的基本概念是 恶性转化涉及不同的信号通路， 必须先确定，然后我们才能知道 治疗性或预防性干预。

The long-term goal of this program project is to improve understanding of the pathogenesis and pathophysiology of childhood cancers and to capitalize on molecular insights gained in the laboratory to devise new means of assessing prognosis and improving therapy. This broad objective is being pursued through five coordinated projects supported by administrative, transgenic, molecular cytogenetic and molecular diagnostic cores. In Project 1 (M. Roussel) the aim is to clarify the role of INK4 inhibitors of the CDK4/CDK6 cyclin D-dependent kinases in the genesis of childhood cancers. Each known member of the INK4 family arrests the progression of cells through the first gap (G1 phase of the cell cycle, but their contribution to tumorigenesis remains to be defined. Project 2 (S. Baker) will address the role of the EWS-ets family of chimeric transcription factors in the aberrant growth and differentiation of Ewing's sarcoma. EWS interacting proteins will be identified and cell types susceptible to transformation by the fusion protein will be defined in transgenic mice. The working hypothesis of Project 3 (J. Downing) is that AML1 fusion proteins contribute to leukemia by interfering with target genes normally regulated by the AML1/CBFbeta complex. This role will be clarified by defining the normal function of the AML1 gene in embryologic and hematopoietic cell development. The intent of Project 4 (D. Shapiro) is to identify the apparently diverse mechanisms by which the PAX3-FKHR oncoprotein transforms myogenic cells leading to alveolar rhabdomyosarcoma. Novel in vitro models have been developed to assess the effects of enforced PAX3-FKHR expression of myogenic differentiation. Project 5 (A.T. Look) will rely on fluorescence in situ hybridization and other molecular approaches to identify and characterize the properties of a putative neuroblastoma suppressor locus on chromosome 1p. This 5-year program seeks to integrate the efforts of leading molecular biologists with comprehensive core services to answer pivotal questions about the mechanisms that drive childhood neoplasia. Its underlying concept is that malignant transformation involves diverse signaling pathways that must be identified before we will know the legitimate targets for therapeutic or preventive intervention.