Fröhling Stefan, Schlenk Richard F, Stolze Ina, Bihlmayr Jörg, Benner Axel, Kreitmeier Sylvia, Tobis Karen, Döhner Hartmut, Döhner Konstanze
Department of Internal Medicine III, University Hospital of Ulm, Robert-Koch-Str. 8, 89081 Ulm, Germany.
J Clin Oncol. 2004 Feb 15;22(4):624-33. doi: 10.1200/JCO.2004.06.060. Epub 2004 Jan 15.
To assess the prognostic relevance of mutations in the CEBPA gene encoding CCAAT/enhancer binding protein alpha (C/EBP alpha) in a large prospective series of younger adults with acute myeloid leukemia (AML) and normal cytogenetics.
The entire CEBPA coding region was sequenced in diagnostic samples from 236 AML patients 16 to 60 years of age with normal cytogenetics who were uniformly treated on two consecutive protocols of the AML Study Group Ulm, and CEBPA mutation status was correlated with clinical outcome.
CEBPA mutations were detected in 36 (15%) of 236 patients. Twenty-one (9%) of 236 patients had mutations predicted to result in loss of C/EBP alpha function. Remission duration and overall survival (OS) were significantly longer for the 36 patients with CEBPA mutations (P =.01 and P =.05, respectively). On multivariate analysis, wild-type CEBPA was an independent prognostic marker affecting remission duration (hazard ratio, 2.85; P =.01) and OS (hazard ratio, 1.87; P =.04). Analysis of cooperating mutations (both types of activating FLT3 mutations and MLL partial tandem duplications) showed that FLT3 mutations had no significant prognostic influence in patients with CEBPA mutations. Furthermore, there was no significant overlap between the subgroup of patients with CEBPA mutation with predicted loss of C/EBP alpha function and patients with FLT3 or MLL mutations, suggesting that CEBPA loss-of-function mutations define a distinct biologic subclass of AML with normal cytogenetics.
Mutant CEBPA predicts favorable prognosis and may improve risk stratification in AML patients with normal cytogenetics.
在一大组具有正常细胞遗传学的年轻急性髓系白血病（AML）成年患者的前瞻性队列中，评估编码CCAAT/增强子结合蛋白α（C/EBPα）的CEBPA基因突变的预后相关性。
对236例年龄在16至60岁、具有正常细胞遗传学的AML患者的诊断样本进行CEBPA编码区全序列测序，这些患者均按照乌尔姆AML研究组的两个连续方案进行治疗，并将CEBPA突变状态与临床结局相关联。
236例患者中有36例（15%）检测到CEBPA突变。236例患者中有21例（9%）发生的突变预计会导致C/EBPα功能丧失。36例CEBPA基因突变患者的缓解期和总生存期（OS）明显更长（分别为P = 0.01和P = 0.05）。多变量分析显示，野生型CEBPA是影响缓解期（风险比，2.85；P = 0.01）和OS（风险比，1.87；P = 0.04）的独立预后标志物。对协同突变（两种激活型FLT3突变和MLL部分串联重复）的分析表明，FLT3突变对CEBPA基因突变患者无显著预后影响。此外，预计C/EBPα功能丧失的CEBPA突变患者亚组与FLT3或MLL突变患者之间无明显重叠，这表明CEBPA功能丧失突变定义了一种具有正常细胞遗传学的AML独特生物学亚类。
突变型CEBPA预示着良好的预后，并可能改善具有正常细胞遗传学的AML患者的风险分层。
