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，但在ALL易感性和治疗结果方面，明显的种族差异仍然存在，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，但对ALL的种族生物学差异的基础科学研究尤其缺乏。如果没有对ALL差异转化研究的实质性投资，这种灾难性疾病将继续不成比例地影响西班牙裔儿童及其家庭。目的/假设我们小组最近对ALL的基因组研究已经为ALL结果的种族差异建立了遗传基础，例如，美洲原住民的遗传血统与复发率密切相关（Nat Genet 43:37）。特别是，ARID5B的遗传变异显著增加了西班牙裔儿童ALL的发病率和复发风险（J clinical oncology, 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ARID5B是ALL治疗结果的种族差异的关键决定因素，通过它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确定ARID5B的药物遗传变异，并机械地描述ARID5B如何影响ALL药物反应。该项目采用综合方法，将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相结合。目标不仅是发现ALL临床相关的预后标志物，而且要了解预后关联产生的生物学。因此，我们将首先在多种族ALL患儿中对ARID5B进行重测序，然后在最先进的儿童肿瘤组ALL试验中对ARID5B进行药物遗传关联研究（约5000名ALL患儿）。最后，我们将利用ALL细胞系、小鼠模型和ALL患儿，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起AL中种族差异的新的生物学机制，并使治疗方法的发展能够克服种族差异。我们研究的长期目标是描述跨种族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ALL的预后。

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.