成人T细胞急性淋巴细胞白血病中NOTCH1突变的特征研究

本研究旨在阐明NOTCH1突变在成人T细胞急性淋巴细胞白血病（T-ALL）中的特征及临床意义。通过对42例成人T-ALL患者外显子（exon）26／异二聚体N末端（HD-N）、exon27／异二聚体c末端（HD-C）、exon28和exon34／脯氨酸-谷氨酸-丝氨酸-苏氨酸（PEST）区域进行扩增、克隆和测序，研究NOTCH1突变的发生率、突变位点和类型、突变与临床和实验室指标的相关性及其预后意义。结果显示，本组成人T-ALL中NOTCH1突变率66．7％（28／42），共发现45种NOTCH1突变，最多见于HD-N（48．9％，22／45）和PEST（40．0％，18／45）；HD-N结构域突变最多位于氨基酸位点1575（L1575P）（25．O％，7／28），PEST结构域突变最多位于氨基酸位点2443（14．3％，4／28）；初诊时白细胞计数大于10×10^9／L者NOTCH1突变组显著高于无突变组（91．7％vs 54．5％，P=0．021）；骨髓原始及幼稚淋巴细胞比例超过50％者突变组显著高于无突变组（95．8％vs 57．1％，P=0．006）；流式免疫表型CDl0阳性表达率突变组显著高于无突变组（51．9％vs0％，P=0．006）），CD15和CD11b阳性表达率突变组显著低于无突变组（分别为5．3％vs 42．9％，P=0．047和0％vs57．1％，P=0．002）。结论：成人T-ALL的NOTCH1突变具有不同于儿童的突变特征和预后意义，而且中国成人T-ALL的NOCH1突变与西方国家相比可能存在差异。

Characteristics of NOTCH1 Mutation in Adult T-cell Acute Lymphoblastic Leukemia

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 NOTCHI 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 CDllb 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 differentcharacteristics and clinical significance from pediatric patients, and the difference between Chinese patients and patients in Western countries is also indicated.