Integrated Systems Biology of Pediatric AML

摘要：急性髓性白血病（AML）是一种罕见的、破坏性的、研究不足的恶性肿瘤，约有20，00例新发病例 美国约有61，000例。虽然强化化疗主要包括阿糖胞苷（也称为阿糖胞苷）， 柔红霉素和依托泊苷已被用于治疗AML超过40年，仅65%、40%和10%的儿童（年龄 <21岁）、成人（年龄21-65岁）和老年（年龄> 65岁）患者分别在诊断后存活5年。应用程序共同PI， Drs. Lamba（药理学）和Pounds（专门研究癌症基因组学的生物统计学家）成功合作 十多年来，他们一直致力于开发AML的方法和发现AML的分子预后因素。我们和其他来自 儿童肿瘤学小组最近对儿童AML的基因组、甲基化组和转录组进行了表征， 与儿童AML的预后相关。庞德博士开发了创新的综合分析 程序，典型相关投影到最有趣的统计证据（CC-PROMISE）， 在罕见疾病小样本量环境中，显著提高了有意义的生物学发现的统计能力; 使用CC-PROMISE，我们发现DNMT 3B甲基化减少和表达增加与 更大的全基因组甲基化负担和更差的预后;将DNMT 3B的发现转化为对 在正在进行的AML 16临床试验（NCT 03164057）中使用去甲基化药物。这些基因组学、表观基因组学和转录组学 特征，沿着微环境和其他因素，在临床上一定会影响AML的蛋白质组和代谢组。 不幸的是，这些相关的方法还没有得到很好的理解。基本上没有研究集中在全面的 在合理的统一治疗患者队列中评估儿童AML的蛋白质组和代谢组。注意 儿童和成人AML之间存在显著的基因组、转录组、甲基化组和预后差异， 将成人AML患者的结果外推至儿童患者似乎合理。因此，在系统级对 因此，需要从分子疾病生物学的角度来制定有效的治疗策略，改善儿童AML的预后。作为 儿科AML基因组、甲基化组和转录组的收集和综合分析的先驱， Lamba博士和Pounds博士在表征蛋白质组和代谢组方面具有独特的优势， 并将其与我们先前收集的分子，治疗和药物的大型储存库相结合。 一系列多中心临床试验的结果数据。因此，在本申请中，我们提出表征全局 代谢物组（aim 1）和蛋白质组（aim 2）在诊断时获得的白血病细胞， 在圣犹达牵头的三项多机构临床试验（AML 02、AML 08和AML 16，患者总数）中评价对结局的影响 n=400）。在目标3中，我们计划开发一个全面的基因组，甲基化组，转录组， 蛋白质组、代谢组和临床预后的儿科AML使用新的方法。这些创新和 一项异常严格的研究将是对儿童AML代谢组和蛋白质组的首次全面评估， 并开发了一种创新的综合分析方法，首次对五种形式的omic数据进行综合分析， 多个临床终点，以获得迄今为止对儿科AML系统生物学的最完整理解。

ABSTRACT: Acute myeloid leukemia (AML) is a rare, devastating, and understudied malignancy with ~20,00 new cases and around 61,000 cases in US. Though intensive chemotherapy primarily consisting of ara C (also known as cytarabine), daunorubicin, and etopside have been used to treat AML for over 4 decades, only 65%, 40%, and 10% of pediatric (age <21), adult (age 21-65), and elderly (age > 65) patients survive 5 years after diagnosis, respectively. Application co-PIs, Drs. Lamba (pharmacology) and Pounds (biostatistician specializing in cancer genomics) have successfully collaborated for over a decade to develop methods and discover molecular prognostic factors for AML. We and other investigators from Children’s Oncology group have recently characterized the genome, methylome, and transcriptome of pediatric AML and associated each of these with prognosis in pediatric AML. Dr. Pounds developed the innovative integrative analysis procedure, canonical correlation with projection onto the most interesting statistical evidence (CC-PROMISE), that dramatically increases statistical power for meaningful biological discovery in a rare-disease small sample size setting; using CC-PROMISE, we discovered that reduced methylation and increased expression of the DNMT3B associates with greater genome-wide methylation burden and worse prognosis; translating the DNMT3B discovery into evaluation of demethylating agents in the ongoing AML16 clinical trial (NCT03164057). These genomic, epigenomic, and transcriptomic features, along with microenvironmental and other factors, must impact the proteome and metabolome of AML in clinically relevant ways which unfortunately are not well understood. There has been essentially no study focused on comprehensive evaluation of the proteome and metabolome of pediatric AML in a reasonable cohort of uniformly treated patients. Noting the marked genomic, transcriptomic, methylomic, and prognostic differences between pediatric and adult AML, it is not plausible to extrapolate finding from adult AML patients to pediatric. Thus an integrated systems-level understanding of the molecular disease biology is needed to develop effective strategies and improve the prognosis of pediatric AML. As pioneers in the collection and integrated analysis of the pediatric AML genome, methylome, and transcriptome, application co-PIs Drs. Lamba and Pounds are uniquely positioned to characterize the proteome and metabolome of pediatric AML and integrate them with our large repository of previously collected molecular, treatment, and outcome data for a series of multi-center clinical trials. Thus, in this application we propose to characterize global metabolome (aim 1) and proteome (aim 2) the leukemic cell obtained at diagnosis for risk stratification and prognosis by evaluating impact on outcome in three St Jude led multi-institute clinical trials (AML02, AML08 and AML16, total patients n=400). In aim 3, we plan to develop a comprehensive integrated view of the genome, methylome, transcriptome, proteome, metabolome, and clinical prognosis of pediatric AML using novel methods. These innovative and exceptionally rigorous studies will be the first comprehensive evaluation of the pediatric AML metabolome and proteome and develop an innovative integrated analysis method to perform the first integrated analysis of five forms of omic data with multiple clinical endpoints to obtain the most complete understanding of pediatric AML systems biology to date.