Lin Zhong-Kun, Zhang Run, Ge Zheng, Liu Juan, Guo Xing, Qiao Chun, Wu Yu-Jie, Qiu Hai-Rong, Zhang Jian-Fu, Li Jian-Yong
Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Provincial People's Hospital, Nanjing 210029, Jiangsu Province, China.
Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Provincial People's Hospital, Nanjing 210029, Jiangsu Province, China. E-mail:
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2013 Dec;21(6):1403-8. doi: 10.7534/j.issn.1009-2137.2013.06.008.
This study was aimed to investigate the characteristics and clinical significance of NOTCH1 mutation in adult T-cell acute lymphoblastic leukemia (T-ALL). Exon 26/N-terminal region of the heterodimerization domain (HD-N) , exon 27/ C-terminal region of the heterodimerization domain (HD-C) , exon 28 and exon 34/ proline-glutamic acid-serine-threonine (PEST) domain of the NOTCH1 gene were amplified, cloned and sequenced in 42 adult patients with T-ALL to identify the frequency, position and type of NOTCH1 mutation, their correlations with laboratorial and clinical parameters, as well as their relevant prognostic significance. The results showed that the frequency of NOTCH1 mutation in this cohort of adult patients was 66.7% (28/42); A total of 45 types of NOTCH1 mutations were identified in present study, most of them were in HD-N (48.9%, 22/45) and PEST (40.0%, 18/45) domains. Mutation in amino acid 1575 (L1575P) was the top one type of mutation in HD-N (25.0%, 7/28), and amino acid 2443 was the most common mutation position in PEST domain (14.3%, 4/28). In newly diagnosed patients, white blood cell (WBC) >10×10(9)/L and blasts in bone marrow > 50% were predominant in patients with NOTCH1 mutation (91.7% vs 54.5%, P = 0.021 and 95.8% vs 57.1%, P = 0.006 respectively). Immunophenotyping analysis indicated that patients with CD10 positive were more in NOTCH1 mutation group than wild-type group (51.9% vs 0%, P = 0.006), whereas patients with CD15 and CD11b positive were less in NOTCH1 mutation group (5.3% vs 42.9%, P = 0.047 and 0% vs 57.1%, P = 0.002 respectively). It is concluded that NOTCH1 mutation in adult T-ALL has different characteristics and clinical significance from pediatric patients, and the difference between Chinese patients and patients in Western countries is also indicated.
本研究旨在探讨成人T细胞急性淋巴细胞白血病（T-ALL）中NOTCH1突变的特征及其临床意义。对42例成人T-ALL患者的NOTCH1基因第26外显子/异二聚化结构域（HD-N）的N端区域、第27外显子/异二聚化结构域（HD-C）的C端区域、第28外显子和第34外显子/脯氨酸-谷氨酸-丝氨酸-苏氨酸（PEST）结构域进行扩增、克隆和测序，以确定NOTCH1突变的频率、位置和类型，它们与实验室及临床参数的相关性，以及其相关的预后意义。结果显示，该队列成人患者中NOTCH1突变频率为66.7%（28/42）；本研究共鉴定出45种NOTCH1突变类型，其中大多数位于HD-N（48.9%，22/45）和PEST（40.0%，18/45）结构域。第1575位氨基酸突变（L1575P）是HD-N中最常见的突变类型（25.0%，7/28），第2443位氨基酸是PEST结构域中最常见的突变位置（14.3%，4/28）。在新诊断患者中，NOTCH1突变患者中白细胞（WBC）>10×10⁹/L和骨髓原始细胞>50%者居多（分别为91.7%对54.5%，P = 0.021；95.8%对57.1%，P = 0.006）。免疫表型分析表明，NOTCH1突变组中CD10阳性患者多于野生型组（51.9%对0%，P = 0.006），而NOTCH1突变组中CD15和CD11b阳性患者较少（分别为5.3%对42.9%，P = 0.047；0%对57.1%，P = 0.002）。结论是，成人T-ALL中的NOTCH1突变与儿童患者具有不同的特征和临床意义，也提示了中国患者与西方国家患者之间的差异。
