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：急性髓样白血病（AML）是一种罕见的，毁灭性的且被理解的恶性肿瘤，〜20,00个新病例 我们大约有61,000例。尽管强化化疗主要由ARA C（也称为Cytarabine）组成，但 daunorubicin和etopside已用于治疗AML超过40年，只有65％，40％和10％的小儿（年龄 <21），成年人（21-65岁）和诊断后5年（年龄> 65岁）的患者分别存活。应用程序CO， 博士。 Lamba（药理学）和磅（专门从事癌症基因组学）的磅（Biostatisticians）已成功合作 十多年来，开发方法并发现AML的分子原型因子。我们和其他调查人员来自 儿童肿瘤学组最近表征了儿科AML和 将其中的每一个与小儿AML的预后相关联。庞德博士开发了创新的综合分析 程序，指向最有趣的统计证据（CC宣传）的投影的规范相关性， 在稀有疾病的小样本量设置下，大大增加了有意义的生物发现的统计能力； 使用CC-促销，我们发现DNMT3B联合的甲基化和增加的表达降低 更大的全基因组甲基化伯恩和预后较差；将DNMT3B发现转化为评估 正在进行的AML16临床试验（NCT03164057）中的脱甲基剂。这些基因组，表观基因组和转录组学 特征以及微环境和其他因素，必须影响临床上AML的蛋白质组和代谢组 不幸的是，相关的方式尚未得到很好的理解。本质上没有研究重点是全面 在合理治疗的患者中，评估小儿AML的蛋白质组和代谢组。注意 小儿和成人AML之间明显的基因组，转录组，甲基甲基组和预后差异，不是 从成年AML患者到小儿发现的发现合理。对系统级的集成理解 需要分子疾病生物学来制定有效的策略并改善小儿AML的预后。作为 小儿AML基因组，甲基组和转录组的收集和综合分析中的先驱 应用程序Co-Pis Drs。 Lamba和磅是独特的定位，可以表征蛋白质组和代谢组 小儿AML，并将其与我们先前收集的分子，治疗和 一系列多中心临床试验的结果数据。在此应用程序中，我们建议表征全局 代谢组（AIM 1）和蛋白质组（AIM 2）在诊断时获得的白血病细胞，以进行风险分层和预后。 评估三项ST裘德LED多个基础临床试验中对结果的影响（AML02，AML08和AML16，总患者 n = 400）。在AIM 3中，我们计划开发有关基因组，甲基组，转录组的全面综合视图， 蛋白质组，代谢组和小儿AML的临床预后使用新方法。这些创新和 非常严格的研究将是对小儿AML代谢组和蛋白质组的首次全面评估 并开发一种创新的综合分析方法，以对五种形式的OMIC数据进行首次集成分析 迄今为止，要获得对小儿AML系统生物学的最完整了解的多个临床终点。