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目的:研究NPM1、CEBPA、FLT3-ITD及c-kit基因突变在正常染色体核型的急性髓细胞白血病(CN-AML)患者中的临床意义。方法:收集112例初诊AML患者骨髓标本,分离单个核细胞(MNCs),提取DNA。采用改良的热处理姬姆萨R显带技术分析染色体核型。运用基因组PCR及测序进行NPM1、CEBPA、FLT3-ITD及c-kit基因突变检测。分析4种突变在CN-AML中的发生率,比较突变型与野生型患者临床特征、生存期及累积复发率的差异。Cox回归分析研究CN-AML患者各项临床特征及突变状态等因素在总生存期(OS)中的预后意义。结果:112例CN-AML患者中NPM1、CEBPA、FLT3-ITD及c-kit的突变率分别为21.4%、21.4%、13.4%和5.4%。NPM1突变型患者的白细胞(WBC)显著高于野生型患者;FLT3-ITD及c-kit突变型患者的血小板(PLT)明显低于野生型患者,而外周血(PB)及骨髓(BM)的原始细胞比例明显高于野生型患者。排除放弃治疗及异基因造血干细胞移植的患者后,孤立的NPM1突变患者的OS较野生型患者明显延长;孤立的CEBPA突变型患者的OS及无病生存期(DFS)均较野生型患者明显延长;孤立的CEBPA突变患者的累积复发率明显低于野生型患者。Cox回归分析结果显示年龄与BM原始细胞比例高是OS独立的预后指标,CEBPA突变状态与OS相关。结论:在CN-AML中存在一定比例的NPM1、CEBPA、FLT3-ITD及c-kit突变,其中NPM1与CEBPA突变率较高。FLT3-ITD及c-kit突变患者具有较低的PLT及较高的原始细胞比例。孤立的NPM1与CEBPA突变与良好预后相关。
Objective: To investigate the clinical significance of NPM1, CEBPA, FLT3-ITD and c-kit gene mutations in patients with normal myeloid leukemia (CN-AML). Methods: Bone marrow samples of 112 newly diagnosed AML patients were collected. Mononuclear cells (MNCs) were isolated and DNA was extracted. Chromosome karyotypes were analyzed using a modified heat-treated Giemsa R-banding technique. Genomic PCR and sequencing were used to detect the mutations of NPM1, CEBPA, FLT3-ITD and c-kit. The incidence of four mutations in CN-AML was analyzed. The clinical characteristics, survival and cumulative recurrence rates of patients with mutant and wild type were compared. Cox regression analysis of the clinical characteristics of CN-AML patients and the status of mutations and other factors in the overall survival (OS) prognostic significance. Results: The mutation rates of NPM1, CEBPA, FLT3-ITD and c-kit in 112 CN-AML patients were 21.4%, 21.4%, 13.4% and 5.4%, respectively. The WBC in patients with NPM1 mutant was significantly higher than that in wild type patients. The PLT in FLT3-ITD and c-kit mutant patients was significantly lower than that in wild type patients, while the peripheral blood (PB) and bone marrow (BM) The proportion of blast cells was significantly higher than in wild type patients. OS patients with isolated NPM1 mutations were significantly longer than those with wild type patients after excluding patients who had been given treatment and allogeneic hematopoietic stem cell transplantation. OS and disease-free survival (DFS) in isolated CEBPA mutant patients were significantly longer than those in wild type patients The cumulative recurrence rate of isolated CEBPA mutation patients was significantly lower than that of wild type patients. Cox regression analysis showed that the high ratio of age to BM blastocyst was an independent prognostic indicator of OS, and the CEBPA mutation status correlated with OS. Conclusion: There are a certain proportion of NPM1, CEBPA, FLT3-ITD and c-kit mutations in CN-AML. The mutation rates of NPM1 and CEBPA are higher. Patients with FLT3-ITD and c-kit mutations have a lower PLT and a higher proportion of blast cells. Isolated NPM1 and CEBPA mutations are associated with a good prognosis.