ARID5B and disparities of childhood leukemia

ARID5B 与儿童白血病的差异

• 批准号: 8975309
• 负责人: Jun J Yang
• 金额: $ 9.85万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-09 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8975309
• 关键词: 6-Mercaptopurine; Acute Lymphocytic Leukemia; Affect; African American; Antimetabolites; Basic Science; Biological; Biology; Budgets; Cell Line; Cells; Child; Childhood Acute Lymphocytic Leukemia; Childhood Leukemia; Clinical Data; Clinical Trials; Collaborations; DNA Resequencing; Data; Disease; Disease susceptibility; Ethnic Origin; Ethnic group; Family; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genets; Genomics; Goals; Health; Hispanic Americans; Hispanics; Incidence; Inherited; Intervention; Investments; Laboratories; Laboratory Study; Link; Lymphocyte; Malignant Childhood Neoplasm; Malignant Neoplasms; Metabolism; Methotrexate; Molecular; Native Americans; Outcome; Pathway interactions; Pediatric Oncology Group; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Pharmacology; Pharmacotherapy; Population; Positioning Attribute; Predisposition; Prognostic Marker; Publications; Race; Relapse; Reporting; Research; Research Personnel; Risk; Sampling; Therapeutic Intervention; Time; Translational Research; Treatment Protocols; Treatment outcome; Variant; Vertebral column; Work; antileukemic agent; base; caucasian American; clinically relevant; cost; cytotoxicity; follow-up; genetic variant; genome wide association study; genome-wide; histone modification; improved; leukemia; leukemia treatment; mouse model; novel; patient oriented; prognostic; prognostic value; prototype; racial and ethnic; racial difference; racial disparity; research study; response; risk variant; therapeutic development; transcription factor; treatment response; tumorigenesis

DESCRIPTION (provided by applicant): Despite dramatic improvement in cure rates of childhood acute lymphoblastic leukemia (ALL), stark racial disparities have persisted in both ALL susceptibility and treatment outcome, e.g. Hispanic children have the highest incidence of ALL and the poorest survival among major race/ethnic groups in the US. While underlying causes of such racial disparities are largely unknown, there is a particular paucity of basic science studies of biological differences in ALL by race. Without substantive investment in translational research of ALL disparity, this catastrophic disease will continue to disproportionally affect Hispanic children and their families. Objective/hypothesis Recent genomic studies of ALL by our group has established a genetic basis for racial disparities in ALL outcome, e.g. Native American genetic ancestry is strongly correlated with relapse rate (Nat Genet 43:237). In particular, ancestry-related genetic variation in ARID5B contributes significantly to the increased ALL incidence and relapse risk in Hispanic children (J Clin Oncol 30:751). Our further mechanistic studies linked ARID5B to response of ALL cells to methotrexate and 6-mercaptopurine, backbone of almost all contemporary ALL treatment regimens. Building upon these preliminary data, we hypothesize that ARID5B is a critical determinant of racial differences in ALL treatment outcome, via its effects on the disposition of and response to antileukemic drugs. The objectives of this project are to comprehensively identify pharmacogenetic variants in ARID5B and to mechanistically describe how ARID5B affects ALL drug response. Approach Taking a comprehensive approach, this project combines patient-oriented pharmacogenetic studies and laboratory-based molecular pharmacology experiments. The goal is to not only to discover clinically relevant prognostic markers in ALL but also to understand the biology from which the prognostic associations arise. Thus, we will first resequence ARID5B in a multiethnic group of children with ALL, followed by pharmacogenetic association studies of ARID5B in state-of-the-art Children's Oncology Group ALL trials (>5,000 children with ALL). Finally, we will mechanistically characterize ARID5B's effects on methotrexate and 6-mercaptopurine disposition and response, using ALL cell lines, mouse models, and in children with ALL. Impact and significance Successful completion of these studies is likely to establish novel biological mechanisms responsible for racial disparities in AL and enable the development of therapeutic approaches to overcome racial gaps. The long-term goal of our research is to characterize genomic features of ALL across race groups, and to implement pharmacogenomics-guided treatment individualization to improve outcome of ALL for all children.

描述（由申请人提供）：尽管儿童期急性淋巴细胞白血病的治愈率显着提高（所有），但在所有易感性和治疗结果中都存在Stark种族差异，例如西班牙裔儿童在美国主要种族/族裔群体中的生存最高，而最糟糕的生存率。尽管这种种族差异的根本原因在很大程度上尚不清楚，但基础科学研究在种族中都存在生物学差异的基础科学研究。如果没有实质性投资所有差异的转化研究，这种灾难性疾病将继续对西班牙裔儿童及其家人产生不成比例的影响。我们小组对所有人的目的/假设最近对所有结果的种族差异建立了遗传基础，例如美国原住民遗传血统与复发率密切相关（NAT Genet 43：237）。特别是，ARID5B中与祖先相关的遗传变异显着促进西班牙裔儿童的所有发生率和复发风险的增加（J Clin Oncol 30：751）。我们的进一步的机械研究将ARID5B与所有细胞对甲氨蝶呤和6-羟基托嘌呤的反应联系起来，这是几乎所有当代所有治疗方案的骨干。在这些初步数据的基础上，我们假设ARID5B是对所有治疗结果中种族差异的关键决定因素，它通过对抗白血病药物的处置和反应的影响。该项目的目标是全面识别ARID5B中的药物遗传学变异，并机械地描述ARID5B如何影响所有药物反应。采用全面方法的方法，该项目结合了面向患者的药物遗传学研究和基于实验室的分子药理学实验。目的是不仅要发现临床相关的预后标记，还要了解预后关联的生物学。因此，我们将首先在拥有所有人的多种族儿童中重新恢复ARID5B，然后在最先进的儿童肿瘤学小组中对ARID5B进行药物遗传学关联研究，所有试验（> 5,000名所有的儿童）。最后，我们将使用所有细胞系，小鼠模型以及所有所有细胞系对ARID5B对甲氨蝶呤和6-丙氨酸的处置和反应的影响。这些研究的影响和显着性成功完成可能建立了负责AL种族差异的新型生物学机制，并能够发展治疗方法以克服种族歧视。我们研究的长期目标是表征所有种族群体的基因组特征，并实施药物基因组学引导的治疗个性化，以改善所有儿童的结果。