ARID5B and disparities of childhood leukemia

描述(申请人提供)：尽管儿童急性淋巴细胞性白血病(ALL)的治愈率显著提高，但在所有易感性和治疗结果方面，明显的种族差异仍然存在，例如，拉美裔儿童的发病率是ALL中最高的，但在美国主要种族/民族中存活率最低。虽然这种种族差异的根本原因在很大程度上是未知的，但对于所有种族的生物差异的基础科学研究尤其匮乏。如果没有对所有差异的转化研究进行实质性投资，这种灾难性的疾病将继续不成比例地影响拉美裔儿童及其家庭。目的/假设本课题组最近对ALL进行的基因组研究为所有结果的种族差异奠定了遗传基础，例如，美洲原住民的遗传祖先与复发率密切相关(NAT Genet 43：237)。特别是，ARID5B的血统相关遗传变异显著增加了拉美裔儿童ALL的发病率和复发风险(J Clin Oncol30：751)。我们进一步的机制研究将ARID5B与所有细胞对甲氨蝶呤和6-巯基嘌呤的反应联系起来，这是几乎所有当代所有治疗方案的主干。在这些初步数据的基础上，我们假设ARID5B是所有治疗结果中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识别ARID5B的药物遗传变异，并机械地描述ARID5B如何影响所有药物的反应。该项目采取综合方法，结合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。我们的目标不仅是在所有患者中发现临床上相关的预后标记物，而且还了解预后相关性产生的生物学基础。因此，我们将首先对ARID5B在ALL儿童的多种族群体中进行重新排序，然后在最先进的儿童肿瘤学组ALL试验中对ARID5B进行药物遗传学研究(&gt；5000名ALL儿童)。最后，我们将利用所有细胞系、小鼠模型和ALL儿童，从机械上表征ARID5B对甲氨蝶呤和6-巯基嘌呤的处置和反应的影响。影响和意义这些研究的成功完成可能会建立新的导致急性白血病种族差异的生物学机制，并能够开发出克服种族差异的治疗方法。我们研究的长期目标是描述所有种族群体的基因组特征，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结果。

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.