ARID5B and disparities of childhood leukemia

描述（由申请人提供）：尽管儿童急性淋巴细胞白血病（ALL）的治愈率显著提高，但ALL易感性和治疗结局仍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，生存率最低。虽然这种种族差异的根本原因在很大程度上是未知的，有一个特别缺乏的基础科学研究的生物学差异，在所有的种族。如果不对ALL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的基因组研究已经建立了ALL结果中种族差异的遗传基础，例如美洲原住民遗传血统与复发率密切相关（Nat Genet 43：237）。特别是，ARID 5 B中与祖先相关的遗传变异显著导致西班牙裔儿童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ARID 5 B与ALL细胞对甲氨蝶呤和6-巯基嘌呤的反应联系起来，这是几乎所有当代ALL治疗方案的支柱。基于这些初步数据，我们假设ARID 5 B是ALL治疗结果种族差异的关键决定因素，通过其对抗白血病药物的处置和反应的影响。该项目的目的是全面识别ARID 5 B的药物遗传学变异，并从机制上描述ARID 5 B如何影响ALL药物反应。该项目采用综合方法，将以患者为中心的药物遗传学研究和以实验室为基础的分子药理学实验相结合。其目标不仅是发现ALL的临床相关预后标志物，而且要了解预后相关性产生的生物学。因此，我们将首先在多种族ALL儿童组中对ARID 5 B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ARID 5 B的药物遗传学关联研究。最后，我们将使用ALL细胞系、小鼠模型和ALL儿童，从机制上描述ARID 5 B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新的生物学机制，负责种族差异的AL，并使治疗方法的发展，以克服种族差距。我们研究的长期目标是描述不同种族ALL的基因组特征，并实施药物基因组学指导的个体化治疗，以改善所有儿童的ALL结局。

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.