PHARMACOGENOMICS OF CHILDHOOD LEUKEMIA (ALL)

描述（由申请人提供）：尽管在过去二十年中取得了实质性进展，但癌症仍然是美国1至15岁儿童疾病死亡的主要原因。急性淋巴细胞白血病（ALL）是最常见的儿童癌症，目前治愈率接近80%。不幸的是，20%的ALL儿童无法通过目前的治疗治愈，使得复发性ALL病例的数量大于大多数儿童癌症新发病例的总数。先前的工作已经确定，新生耐药性是儿童ALL治疗失败的主要原因。然而，这种耐药性的基因组决定因素仍然不清楚。我们最近发现了一些新的基因，这些基因在B系ALL细胞中以显著不同的水平表达，这些细胞对广泛使用的抗白血病药物（泼尼松龙、长春新碱、天冬酰胺酶、柔红霉素）表现出新生耐药，并且它们的表达模式也与治疗结果显著相关。为了评估，三个研究目标扩展了我们先前的发现。第一个科学目标是鉴定赋予儿童ALL对广泛使用的硫嘌呤、巯基嘌呤和硫鸟嘌呤从头耐药的基因。这将是第一个全基因组分析的基因赋予硫嘌呤耐药性，并将提供重要的新的见解，他们是否代表不同的抗白血病药物。第二个目标是确定T-ALL中的基因，这些基因赋予对我们先前在B系ALL中研究的四种药物（泼尼松龙、长春新碱、天冬酰胺酶、柔红霉素）和两种硫嘌呤的新生耐药性。这将产生药物基因组学的见解，为什么T-ALL与大多数治疗方案的预后较差。最终的目的是确定生殖系多态性或表观遗传变化的启动子区的那些基因，差异表达的ALL细胞表现出耐药性，这些抗白血病药物。初步研究已经确定了ALL细胞中mRNA表达与研究的第一个基因（SMARCB 1）的启动子单倍型结构之间的显着关系。重要的是以系统的方式将这些药物基因组学研究扩展到赋予从头耐药性的其他基因。这些发现将继续为治疗失败的基因组决定因素提供重要的新见解，并为开发克服儿童ALL耐药性的策略提供新的靶点。

DESCRIPTION (provided by applicant): Despite substantial progress in the past two decades, cancer remains the leading cause of death by disease in US children between 1 and 15 years of age. Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and cure rates are approaching approximately 80% today. Unfortunately, 20% of children with ALL are not cured with current therapy, making the number of cases of relapsed ALL greater than the total number of new cases of most childhood cancers. Previous work has established that de novo drug resistance is a primary cause of treatment failure in childhood ALL. However, the genomic determinants of such resistance remain poorly defined. We have recently identified a number of new genes that are expressed at a significantly different level in B-lineage ALL cells exhibiting de novo resistance to widely used antileukemic agents (prednisolone, vincristine, asparaginase, daunorubicin), and their pattern of expression was also significantly related to treatment outcome. To assess, three research aims that extend our prior findings. The first scientific aim is to identify genes conferring de novo resistance of childhood ALL to the widely used thiopurines, mercaptopurine and thioguanine. This will be the first genome-wide analysis of genes conferring thiopurine resistance and will provide important new insights into whether they represent distinct antileukemic agents. The second aim is to identify genes in T-ALL that confer de novo resistance to the four agents we have previously studied in B-lineage ALL (prednisolone, vincristine, asparaginase, daunorubicin) and the two thiopurines. This will yield pharmacogenomic insights into why T-ALL has a worse prognosis with most treatment protocols. The final aim is to identify germline polymorphisms or epigenetic changes in the promoter regions of those genes that are differentially expressed in ALL cells exhibiting resistance to these antileukemic agents. Preliminary studies have already identified a significant relation between mRNA expression in ALL cells and the promoter haplotype structure of the first gene investigated (SMARCB1). It is important to extend these pharmacogenomic studies in a systematic way to additional genes conferring de novo drug resistance. These findings will continue to provide important new insights into the genomic determinants of treatment failure and point to novel targets for developing strategies to overcome drug resistance in childhood ALL.