PHARMACOGENOMICS OF CHILDHOOD LEUKEMIA (ALL)

描述(申请人提供)：尽管在过去的二十年里取得了长足的进步，但癌症仍然是美国1至15岁儿童因疾病死亡的主要原因。急性淋巴细胞性白血病(ALL)是儿童最常见的癌症，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方法治愈，这使得复发病例的数量都超过了大多数儿童癌症新发病例的总数。以前的工作已经证实，从头开始的耐药性是儿童ALL治疗失败的主要原因。然而，这种抗性的基因组决定因素仍然没有明确的定义。我们最近发现了一些新的基因，它们在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)表现出从头耐药的B系ALL细胞中的表达水平显著不同，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导致儿童对广泛使用的硫嘌呤、硫代嘌呤和硫鸟嘌呤产生新耐药性的基因。这将是第一次对硫代嘌呤耐药基因进行全基因组分析，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。第二个目的是确定T-ALL中对我们先前在B系ALL中研究的四种药物(强的松龙、长春新碱、天冬酰胺酶、柔红霉素)和两种硫嘌呤产生新的耐药性的基因。这将产生对为什么T-ALL在大多数治疗方案中预后更差的药物基因组学见解。最终目的是确定在所有对这些抗白血病药物具有耐药性的细胞中差异表达的那些基因的种系多态或启动子区的表观遗传学变化。初步研究已经确定了ALL细胞中的mRNA表达与第一个被研究的基因(SMARCB1)的启动子单倍型结构之间的显著关系。重要的是，以系统的方式将这些药物基因组研究扩展到更多与新生耐药有关的基因。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，并为制定克服儿童ALL耐药性的策略指明新的目标。

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.