Prognostic Significance of, and Gene and MicroRNA Expression Signatures Associated With, CEBPA Mutations in Cytogenetically Normal Acute Myeloid Leukemia With High-Risk Molecular Features: A Cancer and Leukemia Group B Study
Prognostic Significance of, and Gene and MicroRNA Expression Signatures Associated With, CEBPA Mutations in Cytogenetically Normal Acute Myeloid Leukemia With High-Risk Molecular Features: A Cancer and Leukemia Group B Study
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DOI：
10.1200/jco.2008.17.5554
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发表时间：
2008-11-01
影响因子：
45.3
通讯作者：
Bloomfield, Clara D.
中科院分区：
文献类型：
--
作者：
Marcucci, Guido;Maharry, Kati;Bloomfield, Clara D.
目的评价CEBPA突变在细胞遗传学正常（CN）急性髓细胞白血病（AML）中的预后意义，并获得CN-AML分子高危亚群白血病发生的生物学见解（FLT 3内部串联重复[ITD]阳性和/或NPM 1野生型），CEBPA突变的发生率显著高于分子低风险子集患者和方法在治疗前筛选175名年龄小于60岁的患有未经治疗的原发性CN-AML的成年人的CEBPA、FLT 3、MLL、WT 1和NPM 1突变以及BAALC和ERG表达水平。基因和microRNA（miRNA）表达谱获得CN-AML分子高危patients.Results CEBPA突变预测更好的无事件（P = 0.007），无病（P = 0.014），和总生存（P = 0.001）独立于其他分子和临床指标。在CEBPA突变的患者中，91%属于CN-AML分子高危组。在该组中，CEBPA突变预测了更好的无事件（P <0.001），无疾病（P = 0.004）和总生存期（P = 0.009），独立于其他分子和临床特征，并与独特的基因和miRNA表达谱相关。这些谱的主要特征是参与红系分化的基因（例如，GATA 1、ZFPM 1、EPOR和GFI 1B）和miRNA（即，miR-181家族）的上调和同源异型盒基因的下调。结论CEBPA突变的治疗前检测可识别具有不同结局的CN-AML患者，特别是在分子高危组中，从而改善了AML这一大型细胞遗传学亚群的基于分子风险的分类。基因和miRNA表达谱分析提供了CN-AML分子高危组白血病发生的见解，表明CEBPA突变与部分红细胞分化相关。J Clin Oncol 26：5078-5087. (C)2008年美国临床肿瘤学会
Purpose To evaluate the prognostic significance of CEBPA mutations in the context of established molecular markers in cytogenetically normal (CN) acute myeloid leukemia (AML) and gain biologic insights into leukemogenesis of the CN-AML molecular high-risk subset (FLT3 internal tandem duplication [ITD] positive and/or NPM1 wild type) that has a significantly higher incidence of CEBPA mutations than the molecular low-risk subset (FLT3-ITD negative and NPM1 mutated).Patients and Methods One hundred seventy-five adults age less than 60 years with untreated primary CN-AML were screened before treatment for CEBPA, FLT3, MLL, WT1, and NPM1 mutations and BAALC and ERG expression levels. Gene and microRNA (miRNA) expression profiles were obtained for the CN-AML molecular high-risk patients.Results CEBPA mutations predicted better event-free (P = .007), disease-free (P = .014), and overall survival (P = .001) independently of other molecular and clinical prognosticators. Among patients with CEBPA mutations, 91% were in the CN-AML molecular high-risk group. Within this group, CEBPA mutations predicted better event-free (P < .001), disease-free (P = .004), and overall survival (P = .009) independently of other molecular and clinical characteristics and were associated with unique gene and miRNA expression profiles. The major features of these profiles were upregulation of genes (eg, GATA1, ZFPM1, EPOR, and GFI1B) and miRNAs (ie, the miR-181 family) involved in erythroid differentiation and downregulation of homeobox genes. Conclusion Pretreatment testing for CEBPA mutations identifies CN-AML patients with different outcomes, particularly in the molecular high-risk group, thus improving molecular risk-based classification of this large cytogenetic subset of AML. The gene and miRNA expression profiling provided insights into leukemogenesis of the CN-AML molecular high-risk group, indicating that CEBPA mutations are associated with partial erythroid differentiation. J Clin Oncol 26: 5078-5087. (C) 2008 by American Society of Clinical Oncology