Genomics of AML Prognosis

AML 预后的基因组学

• 批准号: 10747046
• 负责人: Jatinder K. Lamba
• 金额: $ 7.98万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747046
• 关键词: Acceleration; Achievement; Acute Myelocytic Leukemia; Ara-C; Biological; Childhood Leukemia; Clinical; Clinical Trials; Collaborations; DNMT3B gene; Daunorubicin; Development; Diagnosis; Disease; Disease Resistance; Etoposide; Evaluation; Failure; Foundations; Funding; Gene Expression; Genes; Genomics; International; Legal patent; Leukemic Cell; Methods; Methylation; Molecular; Outcome; Patients; Pharmacology; Procedures; Productivity; Prognosis; Prognostic Factor; Publications; Rare Diseases; Recurrent disease; Research; Resistance; Sample Size; Translating; Translations; Validation; Variant; cancer genomics; chemotherapy; clinical practice; clinically significant; cohort; demethylation; effective therapy; epigenomics; genome wide association study; genome wide methylation; innovation; leukemia treatment; leukemic stem cell; molecular domain; older patient; pediatric patients; prognostic; risk stratification; sound; symposium; transcriptomics

1. ABSTRACT: Acute Myeloid Leukemia (AML) is a heterogeneous disease with a dismal outcome; fewer than 20% of elderly patients and only 50-65% of pediatric patients are cured and survive more than 3 years following diagnosis. Despite this, the standard therapy for AML treatment has relied primarily on an intensive combination of ara- C, daunorubicin, and etoposide (ADE) for over 40 years. Relapsed and resistant disease following treatment with standard therapy (ADE: ara-C, daunorubicin, and etoposide) are the most common clinical failures that occur in treating this disease. 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. During our recently completed second funding cycle, we were very productive with 13 scientific publications, 53 conference presentations, and two pending patents. Our second-cycle scientific achievements include the development of an ara-C SNP score that predicts leukemic cell intracellular levels of ara- CTP, the active form of ara-C the development of 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 to discover 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; the development and initial validation of the six-gene pediatric leukemia stem cell (pLSC6) score (patent pending) and five-gene ADE resistance score (ADE-RS5) score that predict prognosis. In this renewal application, we propose to accelerate our exciting progress by extensively validating the pLSC6 and ADE-RS5 scores to provide a robust scientific foundation to translate them into clinical practice and further developing our understanding of the biological basis of AML development and prognosis into other molecular domains. In the current proposal we seek to accelerate our exciting progress by extensively validating the pLSC6 and ADE-RS5 scores in ~ 4000 patients across 10 independent national and international AML cohorts treated on intensive chemotherapy, to provide a robust scientific foundation for its translation into clinical practice. In aim 2, we propose to perform a clinical outcome-GWAS (CO-GWAS) and establish prognostic genes and variants with a constellation of genomic, epigenomic, and transcriptomic features that associate with clinical outcomes which will undergo thorough mechanistic validation in aim 2. The successful completion of these studies will be scientifically and clinically significant by preparing a sound scientific rationale to incorporate prognostic gene expression scores into the risk stratification of AML patients and revealing additional layers of the molecular basis of AML prognosis to guide the development of more effective therapies.

1. 摘要：急性髓系白血病 (AML) 是一种异质性疾病，预后不佳。少于 20% 的老年患者和仅 50-65% 的儿童患者治愈并存活 3 年以上 诊断。尽管如此，AML 治疗的标准疗法主要依赖于 ara- C、柔红霉素和依托泊苷 (ADE) 已有 40 多年的历史。治疗后疾病复发和耐药 标准疗法（ADE：ara-C、柔红霉素和依托泊苷）是最常见的临床失败 治疗这种疾病。应用联合PI，博士。 Lamba（药理学）和 Pounds（生物统计学家） 癌症基因组学）已成功合作十多年，开发方法并发现分子 AML 的预后因素。在我们最近完成的第二个融资周期中，我们非常富有成效，有 13 科学出版物、53 份会议报告和两项正在申请的专利。我们的第二周期科学 成就包括开发了 ara-C SNP 评分，可预测白血病细胞细胞内 ara-C 的水平 CTP，ara-C 的活性形式，创新的综合分析程序的开发；典范 与最有趣的统计证据（CC-PROMISE）的投影的相关性，显着增加 在罕见疾病小样本量环境中进行有意义的生物学发现的统计功效；使用 CC- 承诺发现 DNMT3B 甲基化减少和表达增加与更大的相关性 全基因组甲基化负担和较差的预后；将 DNMT3B 发现转化为评估 正在进行的 AML16 临床试验中的去甲基化药物；六基因的开发和初步验证 儿童白血病干细胞 (pLSC6) 评分（正在申请专利）和五基因 ADE 抵抗评分 (ADE-RS5) 评分 预测预后。在此续订申请中，我们建议通过广泛地加速我们令人兴奋的进展 验证 pLSC6 和 ADE-RS5 评分，为将其转化为临床提供坚实的科学基础 实践并进一步发展我们对 AML 发展和预后的生物学基础的理解 其他分子域。在当前的提案中，我们寻求通过广泛验证来加速我们令人兴奋的进展 10 个独立的国家和国际 AML 队列中约 4000 名患者的 pLSC6 和 ADE-RS5 评分 进行强化化疗，为其转化为临床实践提供坚实的科学基础。 在目标 2 中，我们建议进行临床结果-GWAS (CO-GWAS) 并建立预后基因和变异 具有与临床结果相关的一系列基因组、表观基因组和转录组特征 将在目标 2 中进行彻底的机制验证。这些研究的成功完成将 通过准备合理的科学原理来纳入预后基因，具有科学和临床意义 将表达评分纳入 AML 患者的风险分层并揭示分子基础的其他层次 AML 预后的研究，以指导开发更有效的疗法。

项目成果

SLC28A3 genotype and gemcitabine rate of infusion affect dFdCTP metabolite disposition in patients with solid tumours.

• DOI: 10.1038/bjc.2013.738
• 发表时间: 2014-01-21
• 期刊: BRITISH JOURNAL OF CANCER
• 影响因子: 8.8
• 作者: Khatri, A.;Williams, B. W.;Fisher, J.;Brundage, R. C.;Gurvich, V. J.;Lis, L. G.;Skubitz, K. M.;Dudek, A. Z.;Greeno, E. W.;Kratzke, R. A.;Lamba, J. K.;Kirstein, M. N.
• 通讯作者: Kirstein, M. N.

CC-PROMISE effectively integrates two forms of molecular data with multiple biologically related endpoints.

CC-PROMISE 有效地将两种形式的分子数据与多个生物学相关的终点整合在一起。

• DOI: 10.1186/s12859-016-1217-0
• 发表时间: 2016
• 期刊: BMC bioinformatics
• 影响因子: 3
• 作者: Cao,Xueyuan;Crews,KristineR;Downing,James;Lamba,Jatinder;Pounds,StanleyB
• 通讯作者: Pounds,StanleyB

Cytochrome P450 2B6*5 Increases Relapse after Cyclophosphamide-Containing Conditioning and Autologous Transplantation for Lymphoma.

• DOI: 10.1016/j.bbmt.2015.02.001
• 发表时间: 2015-05
• 期刊: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
• 作者: Bachanova V;Shanley R;Malik F;Chauhan L;Lamba V;Weisdorf DJ;Burns LJ;Lamba JK
• 通讯作者: Lamba JK

RRM1 and RRM2 pharmacogenetics: association with phenotypes in HapMap cell lines and acute myeloid leukemia patients.

• DOI: 10.2217/pgs.13.131
• 发表时间: 2013-09
• 期刊: Pharmacogenomics
• 影响因子: 2.1
• 作者: Cao X;Mitra AK;Pounds S;Crews KR;Gandhi V;Plunkett W;Dolan ME;Hartford C;Raimondi S;Campana D;Downing J;Rubnitz JE;Ribeiro RC;Lamba JK
• 通讯作者: Lamba JK

Correction: A six-gene leukemic stem cell score identifies high risk pediatric acute myeloid leukemia.

更正：六基因白血病干细胞评分可识别高危儿童急性髓系白血病。

• DOI: 10.1038/s41375-020-0822-0
• 发表时间: 2020
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: Elsayed,AbdelrahmanH;Rafiee,Roya;Cao,Xueyuan;Raimondi,Susana;Downing,JamesR;Ribeiro,Raul;Fan,Yiping;Gruber,TanjaA;Baker,Sharyn;Klco,Jeffery;Rubnitz,JeffreyE;Pounds,Stanley;Lamba,JatinderK
• 通讯作者: Lamba,JatinderK