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%的急性淋巴细胞白血病儿童无法通过目前的治疗治愈，这使得复发性淋巴细胞白血病的病例数超过了大多数儿童癌症的新病例总数。先前的研究已经证实，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明确。我们最近发现了一些新的基因，它们在b系ALL细胞中表达水平显著不同，对广泛使用的抗白血病药物（强的松龙、长春新碱、天冬酰胺酶、柔红霉素）表现出新生耐药性，它们的表达模式也与治疗结果显著相关。为了评估，有三个研究目标扩展了我们之前的发现。第一个科学目标是确定赋予儿童ALL对广泛使用的硫嘌呤、巯基嘌呤和硫鸟嘌呤重新产生耐药性的基因。这将是对硫嘌呤耐药基因的首次全基因组分析，并将为它们是否代表不同的抗白血病药物提供重要的新见解。第二个目标是鉴定T-ALL中赋予我们先前在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）和两种硫嘌呤重新耐药的基因。这将产生药物基因组学见解，以了解为什么T-ALL在大多数治疗方案中预后较差。最终目的是确定在ALL细胞中表现出对这些抗白血病药物的抗性的差异表达的基因的启动子区域的种系多态性或表观遗传变化。初步研究已经确定了ALL细胞中mRNA表达与第一个研究基因（SMARCB1）的启动子单倍型结构之间的显著关系。以系统的方式将这些药物基因组学研究扩展到赋予新生耐药性的其他基因是很重要的。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，并指出开发克服儿童ALL耐药策略的新靶点。

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.