Molecular characterization of normal cytogenetics AML in older patients

老年患者正常细胞遗传学 AML 的分子特征

• 批准号: 7471096
• 负责人: GUIDO MARCUCCI
• 金额: $ 20.25万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7471096
• 关键词: Acute Myelocytic Leukemia; Adult; Adverse effects; Age; Biological Markers; Biology; Blast Cell; Blood; Bone Marrow; CEBPA gene; Cancer and Leukemia Group B; Characteristics; Chemotherapy-Oncologic Procedure; Classification; Clinical; Clinical Management; Cytogenetics; Detection; Diagnosis; Disease; EVI1 gene; Elderly; Employee Strikes; FLT3 gene; Frequencies; Future; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Goals; Hematopoietic; Heterogeneity; Incidence; Karyotype; MLL gene; Malignant - descriptor; Molecular; Molecular Abnormality; Molecular Profiling; Mutation; Myelogenous; NPM1 gene; Oblimersen; Outcome; Patients; Phase III Clinical Trials; Population; Predictive Value; Prognostic Factor; Prognostic Marker; Protocols documentation; Public Health; Randomized; Rate; Research; Risk; Standards of Weights and Measures; Stratification; Subgroup; Supportive care; Therapeutic; Therapeutic Intervention; Therapy Clinical Trials; United States; base; cell growth; chemotherapy; cohort; human old age (65+); improved; novel; novel strategies; novel therapeutics; nucleophosmin; older patient; prognostic; response; therapeutic target

DESCRIPTION (provided by applicant): Recent molecular analyses have revealed at diagnosis, a striking heterogeneity with regard to the presence of acquired gene mutations and changes in gene expression in patients with acute myeloid leukemia (AML) and a normal karyotype, the largest cytogenetic subset (i.e., 40-49%) of AML. Multiple submicroscopic genetic alterations with prognostic significance have been discovered, including internal tandem duplication of the FLT3 gene, partial tandem duplication of the MLL gene, mutations in the NPM1 and CEBPA genes high expression of the ERG and BAALC genes. Application of gene-expression profiling has also identified a gene-expression signature that appears to separate cytogenetically normal AML patients into prognostic subgroups. These and similar future findings are likely to have a major impact on the clinical management of cytogenetically normal AML, not only in prognostication but also in selection of appropriate treatment, since many of the identified genetic alterations constitute or will potentially become targets for specific therapeutic intervention. However, most of the studies that have identified and validated these prognostic markers in younger patients (i.e., <60 years), while their predicting value in older patients (>60 years) with normal cytogenetics AML remains to be fully evaluated. This issue is of paramount importance as in the United States 12.6 AML cases per 100,000 are diagnosed if only adults >65 years are considered and the response rates of older AML patients are significantly worse than those of the younger patients. Although these differences could be related to overrepresentation of several clinical poor-prognostic factors, the contribution of distinct molecular markers in the older group remains to be fully evaluated in order to refine risk-adapted stratification strategies that allocate patients who are not likely to respond to conventional chemotherapy treatment, to investigational therapeutic trials. Using as a platform the Cancer and Leukemia Group B (CALGB) 10201 study, a multicenter phase III trial (CALGB) that randomized older AML patients to intensive chemotherapy w/wo the Bcl-2 antisense Genasense, we propose to conduct definitive analyses that assess the frequency and predictive value of molecular abnormalities in older AML patients with normal cytogenetics. To achieved these goals we are proposing the following specific aims: 1) to determine in older AML patients with normal cytogenetics the frequency and the prognostic value of single-gene markers that have been already shown to be predictive of outcome in younger AML; 2) to identify microarray multi-gene expression signatures that correlate with clinical characteristics at diagnosis and outcome in older AML patients with normal cytogenetics; 3) to identify specific microarray multi-miR expression signatures that correlate with clinical characteristics at diagnosis and outcome in older AML patients with normal cytogenetics. PUBLIC HEALTH RELEVANCE: Acute myeloid leukemia (AML) is a malignant, heterogeneous disease characterized by proliferation with maturation arrest of myeloid blasts in bone marrow and blood. In the United States, the incidence of this disease in adults older than 65 years is elevated and the outcome with current treatment approaches is extremely dismal with <10% of the cases achieving long-term survival. Therefore, novel strategies are highly needed. Here, we propose to characterize older AML patients with normal cytogenetics, the largest subgroup of elderly AML (~50% of the entire elderly AML population) for specific molecular markers that can predict outcome. This approach will ultimately allow patients' stratification into risk-adapted treatments and give to those patients who are unlikely to be cured with standard approaches, the possibility to be treated on studies investigating novel compounds without having to suffer first the side effects of the currently used, but ineffective intensive chemotherapy regimens.

描述（由申请人提供）：诊断时显示的最近的分子分析表明，在急性骨髓性白血病（AML）患者中的存在和基因表达的变化方面，异质性引人注目，正常的核型（正常的核型），是AML的最大细胞遗传学子群（即40-49％）。已经发现了具有预后意义的多个遗传改变，包括FLT3基因的内部串联重复，MLL基因的部分串联重复，NPM1和CEBPA基因中的突变，ERG和BAALC基因的高表达。基因表达分析的应用还确定了一种基因表达特征，该特征似乎将细胞遗传学正常的AML患者分离为预后亚组。这些和类似的未来发现可能会对 细胞遗传学上正常的AML，不仅在预后，而且在选择适当的治疗方面，因为许多已鉴定的遗传改变构成或有可能成为特定治疗干预的靶标。但是，大多数研究都在年轻患者（即<60岁）中鉴定并验证了这些预后标记的大多数研究，而在正常的细胞遗传学AML的老年患者（> 60岁）中，它们的预测价值仍有待充分评估。这个问题至关重要，因为在美国，如果仅考虑成年人> 65岁，并且年龄较大的AML患者的反应率明显比年轻患者的患者差，则每10万例AML病例被诊断为每10万例AML病例。尽管这些差异可能与几个临床差的差异因素的过度代表有关，但较老组的不同分子标记物的贡献仍有待完全评估，以便完善适应风险的分层策略，这些分层策略分配不太可能对常规化学治疗的患者分配对常规化学治疗，对研究治疗试验的反应。使用作为平台，癌症和白血病B组（CALGB）10201研究，这是一项多中心III期试验（CALGB），随机将老年AML患者随机化进行加密化学疗法，并通过Bcl-2反义genasense，我们建议进行定向分析，以评估老年AMLLEC患者的频率和预测值。为了实现这些目标，我们提出了以下特定目的：1）确定在正常细胞遗传学的老年AML患者中，单基因标记物的频率和预后价值已经被证明可以预测年轻AML的结果； 2）确定与正常细胞遗传学的老年AML患者的诊断和结局相关的微阵列多基因表达特征； 3）确定特定的微阵列多-MIR表达特征，这些特征与诊断和结果的临床特征相关的年龄较大的AML正常患者 细胞遗传学。 公共卫生相关性：急性髓细胞性白血病（AML）是一种恶性，异质性疾病，其特征是骨髓和血液中髓样爆炸的成熟停滞。在美国，这种疾病在65岁以上的成年人中的发病率升高，目前的治疗方法的结果极为令人沮丧，<10％的病例占据了长期生存。因此，非常需要新颖的策略。在这里，我们建议表征具有正常细胞遗传学的老年AML患者，这是可以预测结果的特定分子标记物的最大的老年AML亚组（占整个老年AML种群的50％）。这种方法最终将允许患者分层为适应风险的治疗方法，并给那些不太可能使用标准方法治愈的患者，这种可能在研究新型化合物的研究中接受治疗的可能性，而不必首先遭受当前使用的副作用，但有效的强化化学疗法治疗方案。