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）：尽管儿童急性淋巴细胞白血病 (ALL) 的治愈率显着提高，但 ALL 易感性和治疗结果方面仍然存在明显的种族差异，例如在美国主要种族/族裔群体中，西班牙裔儿童的 ALL 发病率最高，且生存率最差。虽然这种种族差异的根本原因在很大程度上尚不清楚，但关于 ALL 中不同种族的生物学差异的基础科学研究特别缺乏。如果不对所有差异的转化研究进行实质性投资，这种灾难性疾病将继续严重影响西班牙裔儿童及其家庭。目的/假设 我们小组最近对 ALL 进行的基因组研究为 ALL 结果的种族差异奠定了遗传基础，例如美洲原住民的遗传血统与复发率密切相关（Nat Genet 43:237）。特别是，ARID5B 中与血统相关的遗传变异显着导致西班牙裔儿童 ALL 发病率和复发风险增加 (J Clin Oncol 30:751)。我们进一步的机制研究将 ARID5B 与 ALL 细胞对甲氨蝶呤和 6-巯基嘌呤（几乎所有当代 ALL 治疗方案的支柱）的反应联系起来。基于这些初步数据，我们假设 ARID5B 通过影响抗白血病药物的处置和反应，是 ALL 治疗结果中种族差异的关键决定因素。该项目的目标是全面鉴定 ARID5B 的药物遗传学变异，并从机制上描述 ARID5B 如何影响 ALL 药物反应。方法 该项目采用综合方法，结合了以患者为导向的药物遗传学研究和基于实验室的分子药理学实验。我们的目标不仅是发现 ALL 中临床相关的预后标志物，而且是了解产生预后关联的生物学原理。因此，我们将首先在多种族 ALL 儿童组中对 ARID5B 进行重新测序，然后在最先进的儿童肿瘤组 ALL 试验（> 5,000 名 ALL 儿童）中进行 ARID5B 的药物遗传学关联研究。最后，我们将使用 ALL 细胞系、小鼠模型以及患有 ALL 的儿童，从机制上表征 ARID5B 对甲氨蝶呤和 6-巯基嘌呤处置和反应的影响。影响和意义 这些研究的成功完成可能会建立导致 AL 种族差异的新生物学机制，并能够开发克服种族差距的治疗方法。我们研究的长期目标是描述跨种族群体 ALL 的基因组特征，并实施药物基因组学指导的个体化治疗，以改善所有儿童 ALL 的治疗结果。