儿童正常核型急性髓系白血病核仁磷酸蛋白和髓系转录因子CCAAT增强子结合蛋白A基因突变的临床研究

NPM1 and CEBPA mutations in pediatric cytogenetically normal acute myeloid leukemia

目的 探讨儿童正常核型急性髓系白血病（CN-AML）中核仁磷酸蛋白（NPM1）和髓系转录因子CCAAT增强子结合蛋白A（CEBPA）基因突变的发生率,并初步了解其临床特征及对预后的影响.方法 收集2009年8月至2012年12月在中国医学科学院血液病医院儿童血液病诊疗中心住院的CN-AML患儿初诊时骨髓单个核细胞,采用基因组DNA-PCR方法分别扩增其NPM1、CEBPA基因,对PCR产物进行测序分析NPM1第12外显子突变、CEBPA基因外显子.回顾性分析这组患儿的临床资料,并研究NPM1突变、CEBPA突变与临床特征、治疗反应之间的关系.结果 本组30例,3例（10％）NPM1突变者均为A型突变,2例（6.7％） CEBPA突变者均为双位点突变,另有3例FLT3/ITD突变患儿.伴NPM1突变或FLT3/ITD突变患儿初诊白细胞计数为102.80×109/L（24.40×109～252.10×109/L）,骨髓幼稚细胞比例为94.0％（88.0％～97.5％）,高于无突变患儿[18.56×109/L（0.77×109 ～ 388.80×109/L）、80.0％ （16.0％ ～98.0％）]（t=2.353,P=0.043;t=3.804,P=0.002）.NPM1或CEBPA突变患儿第1疗程均完全缓解,2年无事件生存率及总生存率均为100％;其余CN-AML患儿2年无事件生存率及总生存率分别为（40.1±11.2）％及（51.8±10.9）％,低于NPM1或CEBPA突变患儿（P值分别为0.044,0.091）.结论 伴NPM1及CEBPA双位点突变CN-AML患儿具有预后良好的趋势.

Objective To evaluate the frequency of the nucleophosmin （NPM1） gene and the CCAAT/enhancer binding protein α gene （CEBPA） through polymerase chain reaction （PCR） array in pediatric patients with cytogenetically normal acute myeloid leukemia （CN-AML） and explore the clinical significances of these mutations.Method Between August 2009 and December 2012,30 children （＜ 16years old） with newly diagnosed CN-AML were included.The clinical characteristics were analyzed in these patients.PCR combined with direct sequencing was used to detect NPM1,CEBPA gene mutations.All the data were statistically analyzed using SPSS17.0 software.Result The gene mutations were detected in each of the 30 patients.NPM1 mutation was positive in three patients （10％） with type A mutation,while CEBPA mutation was positive in two patients （6.7％） with double mutations（TAD,bZIP）.Besides,FLT3/ITD mutation was positive in three patients.Patients with NPM1 or FLT3/ITD had a significantly elevated diagnostic WBC count with a median diagnostic WBC count of 102.80 × 109/L compared with 18.56 × 109/L for the patients without mutations（t =2.353,P =0.043）,as well as the marrow blast percentage（94.0％vs.80.0％,t =3.804,P =0.002）.The complete remission was achieved in all the 3 patients with NPM1 mutations and 2 patients with CEBPA mutations.All the patients with these mutations also achieved 2-year event-free survival （EFS） and 2-year overall survival （OS）,while 2-year EFS and 2-year OS of the other patients were （40.1 ± 11.2） ％ and （51.8 ± 10.9） ％ （P =0.044,0.091,respectively）.Conclusion NPM1 and CEBPA mutations may indicate a favorable prognosis in pediatric CN-AML.