Integrated Systems Biology of Pediatric AML

儿科 AML 的综合系统生物学

• 批准号: 10585163
• 负责人: Jatinder K. Lamba
• 金额: $ 69.4万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585163
• 关键词: 21 year old; Acute Myelocytic Leukemia; Adult; Adult Acute Myeloblastic Leukemia; Age; Ara-C; Azacitidine; Biological; Biology; CRISPR/Cas technology; Cell Line; Characteristics; Childhood; Childhood Acute Myeloid Leukemia; Childhood Leukemia; Classification; Clinical; Clinical Data; Clinical Trials; Collaborations; Collection; Creatinine; Custom; Cytarabine; DNA Sequence Alteration; DNMT3B gene; Data; Daunorubicin; Decitabine; Development; Diagnosis; Diagnostic; Elderly; Enrollment; Environment; Etoposide; Evaluation; Exposure to; Florida; Genome; Genomics; Glucose; Guidelines; Knock-out; Leukemic Cell; Malignant Neoplasms; Methods; Methylation; Molecular; Molecular Disease; Multi-Institutional Clinical Trial; Multiomic Data; Mutation; Outcome; Pathway interactions; Patient risk; Patients; Pediatric Oncology Group; Pediatric cohort; Pharmaceutical Preparations; Pharmacology; Phosphotransferases; Positioning Attribute; Procedures; Prognosis; Prognostic Factor; Prognostic Marker; Proteins; Proteome; Proteomics; Qualifying; Randomized; Rare Diseases; Recommendation; Recurrence; Reporting; Research; Research Personnel; Risk; Saint Jude Children' s Research Hospital; Sample Size; Sampling; Series; System; Systems Biology; Therapeutic Intervention; Translating; Translational Research; Transplantation; Universities; Work; acute myeloid leukemia cell; amino acid metabolism; cancer genomics; chemotherapy; clinical prognosis; clinical translation; clinically relevant; cohort; demethylation; effective therapy; epigenomics; genome wide methylation; improved; innovation; meetings; metabolome; metabolomics; methylome; methylomics; novel; novel therapeutics; pharmacologic; prognostic; repository; risk stratification; screening; success; transcriptome; transcriptomics

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.

摘要：急性髓系白血病(AML)是一种罕见的、破坏性的、未被充分认识的恶性肿瘤，约有20000例新发病例。 在美国大约有61,000例。虽然强化化疗主要由阿糖胞苷(也称为阿糖胞苷)组成， 柔红霉素和依托泊苷用于治疗AML已超过40年，仅占儿科(AGE)的65%、40%和10% 21岁)、成人(21-65岁)和老年(65岁)患者分别在确诊后存活5年。应用协同PI， 兰巴博士(药理学)和庞德博士(专门研究癌症基因组学的生物统计学家)已经成功合作。 十多年来一直致力于研究AML的治疗方法并发现其分子预后因素。我们和其他调查人员来自 儿童肿瘤小组最近确定了儿童AML的基因组、甲基组和转录组的特征，并 其中每一个都与儿童AML的预后有关。庞斯博士开发了创新的综合分析 程序，与对最有趣的统计证据的预测的典型相关性(CC-Promise)，即 在罕见疾病的小样本环境中，极大地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Dnmt3b的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Dnmt3b的发现转化为对 正在进行的AML16临床试验(NCT03164057)中的去甲基剂。这些基因组、表观基因组和转录组 急性髓系白血病的特点，加上微环境和其他因素，在临床上必然会影响其蛋白质组和代谢组。 不幸的是，相关的方式还没有被很好地理解。基本上还没有集中于全面的研究 在统一治疗的合理队列中评估儿童AML的蛋白质组和代谢组。备注 儿童和成人AML之间显著的基因组、转录组、甲基组和预后差异，但不是 将成人AML患者的发现外推到儿科患者似乎是合理的。从而在系统级别上对 儿童急性髓系白血病需要分子疾病生物学研究来制定有效的治疗策略，改善预后。AS 是收集和综合分析儿童AML基因组、甲基组和转录组的先驱， 应用联合PI兰巴博士和庞德博士在描述蛋白质组和代谢组方面具有独特的地位 并将其与我们先前收集的大量分子、治疗和 一系列多中心临床试验的结果数据。因此，在本应用程序中，我们建议将全局 代谢组(AIM 1)和蛋白质组(AIM 2)诊断时获得的白血病细胞，用于危险分层和预后 评估圣裘德领导的三个多研究所临床试验(AML02、AML08和AML16，总患者)对结果的影响 N=400)。在目标3中，我们计划开发基因组、甲基组、转录组、 用新方法研究儿童急性髓系白血病的蛋白质组、代谢组和临床预后。这些创新和 异常严格的研究将是对儿童AML代谢组和蛋白质组的第一次全面评估 并开发了一种创新的综合分析方法，首次对五种形式的基因组数据进行综合分析 多个临床终点，以获得迄今为止对儿科AML系统生物学最完整的了解。