Molecular Characterization and Risk Stratification of Acute Myeloid Leukemia

急性髓系白血病的分子特征和风险分层

• 批准号: 7715168
• 负责人: CLARA D BLOOMFIELD
• 金额: $ 32.02万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715168
• 关键词: 2 year old; Acute Myelocytic Leukemia; Age; Biology; Blood; Bone Marrow; CEBPA gene; Cancer and Leukemia Group B; Characteristics; Chromosome abnormality; Classification; Clinical; Clinical Management; Companions; Core-Binding Factor; Cytogenetics; Data; Diagnosis; Disease; EVI1 gene; Employee Strikes; Enrollment; FLT3 gene; Frequencies; Future; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Goals; Hematopoietic; Heterogeneity; Institution; Instruction; Laboratories; MicroRNAs; Molecular; Molecular Abnormality; Molecular Cytogenetics; Molecular Profiling; Mutation; NPM1 gene; Outcome; Patients; Population; Predictive Value; Process; Prognostic Marker; Reporting; Research; Risk; Stratification; Subgroup; Therapeutic; Therapeutic Intervention; Therapy Clinical Trials; Treatment Protocols; Tyrosine Kinase Inhibitor; Work; base; cancer cell; cell growth; cohort; design; genome-wide; improved; insight; leukemia; leukemia tissue bank; new therapeutic target; novel; novel strategies; older patient; patient population; prognostic; programs; treatment response; treatment strategy

Recent molecular analyses have revealed at diagnosis, a striking heterogeneity with regard to the presence of acquired, prognostic chromosome aberrations, gene mutations and changes in gene expression in patients with acute myeloid leukemia (AML). Application of gene and microRNA-expression profiling has also identified expression signatures that appear to stratify AML patients within specific cytogenetic subsets into prognostic subgroups. These and similar future findings are likely to have a major impact on the clinical management of AML, not only for the prognostication process but also for the selection of appropriate treatments, since many of the identified genetic alterations constitute or will potentially become targets for specific therapeutic intervention. Using as a platform the Cancer and Leukemia Group B (CALGB) upfront treatment studies, we propose here to conduct definitive analyses that assess the frequencies and prognostic values of molecular abnormalities in a large population of AML patients. Further, we will integrate the information derived from the analysis of prognostic cytogenetic aberrations and gene mutations with that derived from the corresponding genome wide gene and microRNA expression profiles in order to gain biologic insights into leukemogenic mechanisms and identify "integrated functional signatures" that stratify patients into subsets "targetable" with specific therapeutic programs. We will achieve these goals through three Specific Aims: 1. To determine the frequency of molecular aberrations {e.g., FLT3 ITD, MLL PTD, NPM1, WT-1, CEBPA, RAS, KIT mutations and aberrant BAALC. ERG, FLT3, MNI and EVI1 over- expression) at diagnosis and to correlate them with clinical and laboratory characteristics and outcome in distinct cytogenetic subgroups of younger and older AML patients enrolled on CALGB treatment protocols; 2. To identify specific genome wide gene expression signatures at diagnosis and to correlate them with clinical and laboratory characteristics and outcome in distinct cytogenetic and molecular subgroups of younger and older AML patients enrolled on CALGB treatment protocols; 3. To identify specific genome wide microRNA expression signatures at diagnosis and to correlate them with clinical and laboratory characteristics and outcome in distinct cytogenetic and molecular subgroups of younger and older AML patients enrolled on CALGB treatment protocols. We anticipate that completion of this research plan will allow risk-adapted stratification of AML patients into "personalized" treatment protocols designed to target the aberrant "functional" hematopoietic gene signatures that characterize distinct subsets of AML. RELEVANCE (See instructions): Acute myeloid leukemia (AML) is one ofthe most common types of leukemia and is characterized by maturation arrest and proliferation of malignant cells in bone marrow and blood. Despite recent progress, most of patients die of their disease. Therefore, novel approaches that improve the outcome of these patients are highly needed. Here, we propose to characterize malignant cells from AML patients for genetic defects that can predict outcome. This approach will ultimately allow identification of subgroups of AML that will respond to specific and "personalized" treatments thereby improving the currently poor clinical outcome of these patients.

最近的分子分析显示，在诊断，一个显着的异质性方面的存在， 获得性、预后性染色体畸变、基因突变和基因表达变化， 急性髓性白血病（AML）患者。基因和microRNA表达谱的应用 还鉴定了在特定的细胞遗传学亚群中对AML患者进行分层的表达特征 分为预后亚组。这些和类似的未来发现可能会对临床产生重大影响。 AML的管理，不仅适用于验证过程，而且适用于选择适当的 治疗，因为许多鉴定的遗传改变构成或将潜在地成为靶点， 具体的治疗干预。以癌症和白血病组B（CALGB）为平台， 治疗研究，我们建议在这里进行明确的分析，评估频率和 分子异常在大群AML患者中的预后价值。此外，我们将整合 从预后细胞遗传学畸变和基因突变分析中获得的信息， 从相应的全基因组基因和microRNA表达谱中获得， 白血病发生机制的生物学见解，并确定分层的“综合功能特征”， 将患者分成具有特定治疗方案的“靶向”子集。我们将通过以下方式实现这些目标： 三个具体目标：1。为了确定分子畸变的频率（例如，FLT3 ITD，MLL PTD， NPM 1、WT-1、CEBPA、RAS、KIT突变和异常BAALC。ERG、FLT 3、MNI和EVI 1超过- 表达），并将其与临床和实验室特征及结果相关联， 参加CALGB治疗方案的年轻和老年AML患者的不同细胞遗传学亚组; 2.在诊断时识别特定的全基因组基因表达特征，并将其与 不同的细胞遗传学和分子亚组的临床和实验室特征和结果 参加CALGB治疗方案的年轻和老年AML患者; 3.为了识别特定的基因组 在诊断时广泛的microRNA表达特征，并将其与临床和实验室 年轻和老年AML不同细胞遗传学和分子亚组的特征和结局 接受CALGB治疗方案的患者。我们预计，这项研究计划的完成将 允许将AML患者进行风险适应性分层，以制定“个性化”治疗方案， 异常的“功能性”造血基因特征，其表征AML的不同子集。 相关性（参见说明）： 急性髓细胞白血病（AML）是最常见的白血病类型之一，其特征在于成熟 抑制和增殖骨髓和血液中的恶性细胞。尽管最近取得了进展，但大多数患者 死于疾病。因此，非常需要改善这些患者结局的新方法。 在这里，我们建议对AML患者的恶性细胞进行遗传缺陷表征， 结果。这种方法最终将允许识别AML亚组，这些亚组将对特定和 “个性化”治疗，从而改善这些患者目前不良的临床结果。