PHARMACOGENOMICS OF CHILDHOOD LEUKEMIA (ALL)

儿童白血病的药物基因组学（全部）

• 批准号: 7916916
• 负责人: WILLIAM E EVANS
• 金额: $ 66.15万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7916916
• 关键词: 15 year old; 6-Mercaptopurine; Acute Lymphocytic Leukemia; Address; Award; Bite; Cause of Death; Cells; Child; Childhood Acute Lymphocytic Leukemia; Childhood Leukemia; Classification; Clinical; Data; Daunorubicin; Disease; Drug resistance; Epigenetic Process; Evolution; Exhibits; Funding; Gene Expression; Genes; Genetic Polymorphism; Genomics; Haplotypes; Instruction; Journals; Malignant Childhood Neoplasm; Malignant Neoplasms; Methylation; Nature; Newly Diagnosed; Pattern; Peer Review; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Productivity; Promoter Regions; Publications; Relapse; Research; Research Personnel; Research Support; Resistance; Running; SMARCB1 gene; Solid; Structure; Study Section; Thioguanine; Time; Treatment Failure; Treatment Protocols; Treatment outcome; Uncertainty; United States National Institutes of Health; Vincristine; Work; antileukemic agent; asparaginase; base; drug metabolism; genome wide association study; genome-wide analysis; insight; interest; mRNA Expression; novel; outcome forecast; prednisolone; programs; promoter; thiopurine

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.

描述（由申请人提供）：尽管过去二十年取得了重大进展，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，目前治愈率已接近 80% 左右。不幸的是，20% 的 ALL 儿童无法通过当前治疗治愈，这使得复发性 ALL 病例数比大多数儿童癌症的新发病例总数还要多。先前的工作已确定新发耐药性是儿童 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基因，它们在 B 系 ALL 细胞中以显着不同的水平表达，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）表现出从头耐药性，并且它们的表达模式也显着不同。与治疗结果有关。为了评估，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使儿童 ALL 对广泛使用的硫嘌呤、巯嘌呤和硫鸟嘌呤具有从头抗性的基因。这将是首次对赋予硫嘌呤抗性的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。第二个目标是鉴定 T-ALL 中的基因，这些基因赋予我们之前在 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）和两种硫嘌呤的从头耐药性。这将产生药物基因组学见解，解释为什么 T-ALL 在大多数治疗方案中预后较差。最终目的是鉴定在对这些抗白血病药物表现出抗性的所有细胞中差异表达的那些基因的启动子区域中的种系多态性或表观遗传变化。初步研究已经确定 ALL 细胞中 mRNA 表达与所研究的第一个基因 (SMARCB1) 的启动子单倍型结构之间存在显着关系。以系统的方式将这些药物基因组学研究扩展到赋予新耐药性的其他基因非常重要。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 耐药性的策略指出新的目标。