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

基本信息

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
项目类别：
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

项目摘要

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，在诊断时，存在显着的异质性获得性、预后性染色体畸变、基因突变和基因表达变化急性髓系白血病（AML）患者。基因和 microRNA 表达谱的应用还确定了似乎将 AML 患者分层到特定细胞遗传学子集中的表达特征分为预后亚组。这些以及类似的未来发现可能会对临床产生重大影响 AML 的管理，不仅用于预测过程，还用于选择适当的治疗方案治疗，因为许多已识别的基因改变构成或可能成为治疗的目标具体的治疗干预。预先使用癌症和白血病 B 组 (CALGB) 作为平台治疗研究，我们在此建议进行明确的分析，评估频率和大量 AML 患者中分子异常的预后价值。进一步，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衍生自相应的全基因组基因和 microRNA 表达谱，以获得对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” 将患者分为具有特定治疗方案“可靶向”的子集。我们将通过以下方式实现这些目标三个具体目标： 1. 确定分子畸变的频率（例如，FLT3 ITD、MLL PTD、 NPM1、WT-1、CEBPA、RAS、KIT 突变和异常 BAALC。 ERG、FLT3、MNI 和 EVI1 过度表达）在诊断时并将其与临床和实验室特征以及结果相关联参加 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细胞遗传学和分子亚组的临床和实验室特征及结果参加 CALGB 治疗方案的年轻和老年 AML 患者； 3. 鉴定特定基因组诊断时广泛的 microRNA 表达特征并将其与临床和实验室相关联年轻和老年 AML 不同细胞遗传学和分子亚组的特征和结果参加 CALGB 治疗方案的患者。我们预计该研究计划的完成将允许对 AML 患者进行风险适应分层，以制定针对目标的“个性化”治疗方案异常的“功能性”造血基因特征是 AML 不同亚型的特征。相关性（参见说明）：急性髓系白血病 (AML) 是最常见的白血病类型之一，其特点是成熟骨髓和血液中恶性细胞的抑制和增殖。尽管最近取得了进展，但大多数患者死于他们的疾病。因此，非常需要改善这些患者预后的新方法。在这里，我们建议对 AML 患者的恶性细胞进行遗传缺陷特征分析，以预测结果。这种方法最终将允许识别 AML 亚组，这些亚组将对特定的和 “个性化”治疗从而改善了这些患者目前较差的临床结果。