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）：尽管在过去的二十年中取得了长足的进展，但癌症仍然是1至15岁的美国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，如今治愈率约为80％。不幸的是，有20％的患有当前疗法的儿童没有治愈，这使得复发的病例数量大于大多数儿童期癌症的新病例总数。先前的工作已经确定，从头耐药性是童年时期治疗失败的主要原因。但是，这种抗性的基因组决定因素仍然很差。我们最近确定了许多新基因，这些基因在B-linege中以显着不同的水平表达的所有细胞表现出对广泛使用的抗毒剂的耐药性（泼尼松龙，vincristine，vincristine，daunorubicin）的表达方式，其表达方式也与治疗结果显着相关。为了评估，三个研究目的扩展了我们先前的发现。第一个科学目的是鉴定赋予童年从头抗性的基因，所有基因均供广泛使用的硫代嘌呤，胃嘌呤和硫代氨酸。这将是对硫嘌呤耐药性赋予基因的首次基因组分析，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。第二个目的是鉴定T-all中的基因，这些基因赋予我们先前在B-Linege中研究的四种药物（泼尼松龙，长春新碱，天冬酰胺酶，Daunorubicin）和两个硫嘌呤中研究的四种药物。这将产生药物基因组学的见解，说明为什么大多数治疗方案对T-All的预后较差。最终的目的是鉴定在所有表现出对这些抗白血病药物抗性的细胞中差异表达的基因启动子区域的生殖线多态性或表观遗传变化。初步研究已经确定了所有细胞中mRNA表达与研究的第一个基因的启动子单倍型结构之间的显着关系（SMARCB1）。重要的是要以系统的方式扩展这些药物基因组学研究，以给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，并指出了制定策略以克服童年时期耐药性的新目标。