王晓丽 刘永华 江锦红

[摘要] 目的 探討IDH1-R123与Notch1双突变对儿童急性T淋巴细胞白血病（ALL）的作用及机制。 方法 选择2016年5月～2017年12月丽水市人民医院儿童ALL患者58例作为对象，所有患者入院后均完成IDH1-R123与Notch1双突变基因测序，确定IDH1-R123与Notch1双突变在儿童急性T淋巴细胞白血病中的突变率及突变特征，入组患者均给予诱导、巩固及维持治疗，两组治疗后均完成24个月随访，比较突变儿童与非突变儿童生化指标、临床特征及预后。 结果 58例儿童ALL患者中33例IDH1-R123与Notch1双突变，突变率为56.90%;突变儿童血WBC计数、平均血红蛋白高于非突变儿童（P<0.05）;突变儿童平均血小板数低于非突变儿童（P<0.05）;ALL IDH1-R123突变25例，占43.10%，突变位于WD40区域，且均为点突变;Notch1突变8例，占13.79%，突变位点主要位于HD区域和PEST结构域。其中，HD突变5例，占62.50%，均为氨基酸位点为233;PEST结构域3例，占37.50%;突变儿童与非突变儿童6个月、12个月生存率无统计学意义（P>0.05）;突变儿童18个月、24个月生存率低于非突变儿童（P<0.05）。 结论 IDH1-R123与Notch1双突变在儿童急性T淋巴细胞白血病中突变率较高，且与患者不良预后有关，有助于指导临床诊疗。

[关键词] IDH1-R123突变;Notch1突变;儿童急性T淋巴细胞白血病;临床特征

[中图分类号] R733.71 R730.7          [文献标识码] A          [文章编号] 1673-9701（2020）18-0015-04

Mechanism of IDH1-R123 and Notch1 mutations in pediatric acute T lymphocytic leukemia

WANG Xiaoli   LIU Yonghua   JIANG Jinhong

Department of Hematology， Lishui People's Hospital in Zhejiang Province， Lishui   323000， China

[Abstract] Objective To investigate the effect and mechanism of IDH1-R123 and Notch1 double mutations on pediatric acute T lymphocytic leukemia（ALL）. Methods From May 2016 to December 2017， 58 children with ALL in Lishui People's Hospital were selected as subjects. All patients completed IDH1-R123 and Notch1 double mutation genes sequencing after admission， so as to determine the mutation rate and mutation characteristics of IDH1-R123 and Notch1 double mutations in pediatric acute T lymphocytic leukemia. All patients were given induction， consolidation and maintenance for treatments. The two groups were followed up for 24 months after treatment. The biochemical indicators， clinical characteristics， and prognosis of children with mutation and non-mutation were compared. Results Among the 58 children with ALL， there were 33 cases with IDH1-R123 and Notch1 double mutations， and the mutation rate was 56.90%. The blood WBC count and average hemoglobin in the children with mutation were higher than those of children without mutation（P<0.05）. The average platelet count of children with mutation was lower than that of children without mutation（P<0.05）. There were 25 cases of ALL IDH1-R123 mutations， accounting for 43.10%. The mutations were located in the WD40 region and were all point mutations. There were 8 cases of notch1 mutation， accounting for 13.79%. The mutation sites were mainly located in the HD region and the PEST domain. Among them， there were 5 cases of HD mutations， accounting for 62.50%， which were all at the amino acid site of 233; there were 3 cases in PEST domain， accounting for 37.50%. The differences in the 6-month and 12-month survival rates of children with mutation and without mutation were not statistically significant（P>0.05）. The survival rate of children with mutation at 18 and 24 months was lower than that of children without mutation（P<0.05）. Conclusion IDH1-R123 and Notch1 double mutations have a higher mutation rate in children with acute T lymphocytic leukemia， and are associated with poor prognosis of patients， which can help guide clinical diagnosis and treatment.

[Key words] IDH1-R123 mutations; Notch1 mutation; Pediatric acute T lymphocytic leukemia; Clinical characteristics

急性T淋巴细胞白血病（Acute T lymphocytic leukemia，ALL）是一种起源于淋巴细胞的B系、T系细胞在骨髓内异常增生的恶性肿瘤[1]。异常增生的原始细胞能在骨髓聚集并抑制正常造血功能，严重者可侵及骨髓外组织，影响患者健康、生活[2]。数据报道显示[3]：ALL好发于0～9岁儿童，占儿童白血病的70.0%以上，且临床上根据ALL不同生物学特征制定相应的治疗方案能获得良好的效果，80.0%儿童及30.0%成人能获得长期无病生存，亦具有治愈可能。Notch1信号通路异常在ALL中发生率为50.0%以上，多发生在HD区（异二聚体结构域）和PEST结构域[富含脯氨酸（Proline-rich，P）及谷氨酰胺（Glutamine，E）中[4]]。临床研究表明[5]：Notch1信号通路异常激活的另一个重要机制为IDH1-R123发生突变，导致Notch1信号泛素连接酶介导的降解受到抑制。而IDH1-R123突变主要发生在WD40结构域。IDH1-R123与Notch1信号通路突变可能对ALL儿童预后产生影响，但是具体机制尚未明确[6]。……