Marcucci Guido, Maharry Kati, Radmacher Michael D, Mrózek Krzysztof, Vukosavljevic Tamara, Paschka Peter, Whitman Susan P, Langer Christian, Baldus Claudia D, Liu Chang-Gong, Ruppert Amy S, Powell Bayard L, Carroll Andrew J, Caligiuri Michael A, Kolitz Jonathan E, Larson Richard A, Bloomfield Clara D
Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
J Clin Oncol. 2008 Nov 1;26(31):5078-87. doi: 10.1200/JCO.2008.17.5554. Epub 2008 Sep 22.
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).
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.
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.
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.
评估在细胞遗传学正常（CN）的急性髓系白血病（AML）中，CEBPA突变在既定分子标志物背景下的预后意义，并深入了解CN-AML分子高危亚组（FLT3内部串联重复[ITD]阳性和/或NPM1野生型）白血病发生的生物学机制，该亚组CEBPA突变发生率显著高于分子低危亚组（FLT3-ITD阴性且NPM1突变）。
对175例年龄小于60岁、未经治疗的原发性CN-AML成年患者进行治疗前筛查，检测CEBPA、FLT3、MLL、WT1和NPM1突变以及BAALC和ERG表达水平。获取CN-AML分子高危患者的基因和微小RNA（miRNA）表达谱。
CEBPA突变可独立于其他分子和临床预后因素预测更好的无事件生存（P = 0.007）、无病生存（P = 0.014）和总生存（P < 0.001）。在CEBPA突变患者中，91%属于CN-AML分子高危组。在该组中，CEBPA突变可独立于其他分子和临床特征预测更好的无事件生存（P < 0.001）、无病生存（P = 0.004）和总生存（P = 0.009），并与独特的基因和miRNA表达谱相关。这些表达谱的主要特征是参与红系分化的基因（如GATA1、ZFPM1、EPOR和GFI1B）和miRNA（即miR-181家族）上调，以及同源框基因下调。
CEBPA突变的预处理检测可识别出预后不同的CN-AML患者，尤其是在分子高危组，从而改进基于分子风险的AML这一大型细胞遗传学亚组的分类。基因和miRNA表达谱分析为CN-AML分子高危组的白血病发生机制提供了见解，表明CEBPA突变与部分红系分化相关。
