GROWTH CONTROL IN PEDIATRIC TUMORS

这一计划的一个主要目标是分析，在 分子水平，其中控制生长的因素最多 常见的儿童恶性肿瘤(白血病、神经母细胞瘤和软组织 组织肿瘤)，以便改进未来的治疗和预后 接近了。另一个目标是定义基因改变 在与癌症表型有关的体细胞内 自然发生的儿科恶性肿瘤。 急性非淋巴细胞白血病的独特遗传改变 (ANLL)和前B细胞急性淋巴细胞白血病(Pre-B-ALL) 将被描述为。这些更改将被利用来监控 白血病患者微小残留病的程度 正在接受化疗。在ANLL的情况下， 因此，激活的ras癌基因，聚合酶链的偶联 对产生的反应和选择性寡核苷酸筛选 重组文库将被用来评估 在治疗结束前最小程度的残留疾病。在 Pre-B ALL伴t(9；22)易位，结构性 涉及BCR-ABL融合产品的修改将是 以克隆和测序为特征。这一方法将 确定bcr断裂点；使用cdna克隆和测序。 这种方法将识别BCR断点；使用适当的 寡核苷酸探针将允许有效地扩增 Bcr/abl易位，可用于检测和定量 残留的白血病细胞。分子生物学特性的研究 用倒场凝胶电泳法进行染色体易位， 基因组克隆和染色体行走也将是 骨肉瘤和横纹肌肉瘤的研究进展 最终的目标是确定那些导致 这些疾病的恶性进展。 同样的软组织肿瘤，以及神经母细胞瘤， 用来确定血小板衍生品所起的作用 生长因子受体和神经生长因子受体 控制正常和异常的细胞生长和 差异化。在这些实体肿瘤中，最终目标是 了解异常生长因子受体的作用 在促进细胞异常生长方面的表达。 这些异常的特征可以在临床上提供 这些肿瘤的重要预后变量。

A major goal of this proposed program is the analysis, at the molecular level, of the factors that control growth of the most common childhood malignancies (leukemias, neuroblastomas and soft tissue tumors) in order to refine future therapeutic and prognostic approaches. An additional goal is to define genetic alterations within somatic cells that contribute to the cancerous phenotype in naturally occurring pediatric malignancies. Distinct genetic alterations in acute non-lymphocytic leukemia (ANLL) and in pre-B cell acute lymphocytic leukemias (pre-B-ALL) will be characterized. These changes will be exploited to monitor the extent of minimal residual disease of leukemia patients undergoing chemotherapy. In the case of ANLL with a mutated, and thus, activated ras oncogene, coupling of the polymerase chain reaction to generation and selective oligonucleotide screening of recombinant libraries will be utilized to evaluate the extent of minimal residual disease before completion of treatment. In the case of pre-B ALL with the t(9;22) translocation, the structural alterations involving the bcr-abl fusion product will be characterized by cDNA cloning and sequencing. This approach will identify the bcr break point; use of cDNA cloning and sequencing. This approach will identify the bcr break point; use of suitable oligonucleotide probes will allow efficient amplification of the bcr/abl translocation and be useful in detection and quantitation of residual leukemia cells. Molecular characterization of chromosomal translocation using inverted field gel electrophoresis, genomic cloning and chromosomal walking will also be the theme of the proposed studies in osteosarcomas and rhabdomyosarcomas with the final aim of identifying those genes responsible for the malignant progression of these diseases. The same soft tissue tumors, as well as neuroblastomas, will be utilized to determine the role played by the platelet-derived growth factor receptor and by the nerve growth factor receptor in controlling both normal and abnormal cellular growth and differentiation. In these solid tumors, the ultimate goal is to understand the contribution of abnormal growth factor receptor expression in contributing to abnormal cellular growth. Characterization of these abnormalities may provide clinically important prognostic variables for these tumors.