Ig/TCR基因重排在儿童急性T淋巴细胞白血病中的表达模式特点

doi:10.3969/j.issn.1673-5501.2019.02.006

摘要/Abstract

摘要： 目的探讨免疫球蛋白(Ig)/ T细胞受体(TCR)基因重排在儿童急性T淋巴细胞白血病(T-ALL)中的表达模式特点及其与临床生物学特征的相关性。方法回顾性纳入首都医科大学附属北京儿童医院(我院)2005年1月1日至2008年12月31日收治的初治T-ALL患儿,分析其初诊时骨髓单个核细胞的Ig/TCR基因重排情况,根据重排情况分为阳性组和阴性组,比较不同组别的临床生物学特征。结果 ①52例儿童T-ALL中男37例(71.2%),入院时中位年龄8.0(1.8~16.0)岁,初诊时WBC中位数为140.5(2.7~667.1)×10⁹·L^-1,中危38例(73.1%)、高危14例(26.9%)。中位随访时间136.3(1.2~171.7)个月,长期完全缓解38例(73.1%)、复发10例(19.2%),其他原因死亡4例(7.7%)。②TCRB、TCRG、TCRD和IgH克隆性基因重排的发生率分别为85%、85%、38%和21%,94%的患儿检出至少1种基因重排,88%的患儿检出至少2种基因重排。TCRB、TCRD、TCRG和IgH重排分别以完全性V_β-(D_β)-J_β、V_δ-J_δ、V_γⅠ-J_γ1.3/2.3和D_H-J_H不完全重排为主。各种重排的胚系片段使用和连接区序列极具多样性。③ 10例复发患儿中有6例检测了复发时的Ig/TCR基因重排模式,4例与初诊时完全一致,2例发生改变。④SIL-TAL1融合基因阳性率在11例IgH重排阳性患儿中0%(0/14),在41例IgH重排阴性患儿中为34.1%(14/41),P=0.025。⑤TCRB基因重排阳性组高危比例(20.5%,9/44)低于阴性组(62.5%,5/8),P=0.025。TCRB或TCRG基因重排阳性组第33 d缓解率(89.4%,42/44)高于阴性组(10.6%,5/8),P=0.022,第78 d MRD水平≥10^-3的比例(10.8%,4/37)低于阴性组(50.0%,3/6),P=0.045。结论儿童T-ALL初诊时Ig/TCR克隆性基因重排的胚系片段使用和连接区序列极具多样性,有助于进一步性MRD 检测标志的筛选。

关键词: T细胞受体, 儿童急性T淋巴细胞白血病, 基因重排, 免疫球蛋白

Abstract: Objective To investigate the characteristics of immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangement patterns in childhood T-cell acute lymphoblastic leukemia(T-ALL), and its correlation with the clinical and biological characteristics of the patients.Methods The study included 52 newly diagnosed pediatric T-ALL patients enrolled at Beijing Children's Hospital from January 1st, 2005 to December 31th, 2008. Analyze the Ig/TCR gene rearrangement of bone marrow mononuclear cells at diagnosis, including the incidence of TCRB, TCRG, TCRD and IgH gene rearrangements and types, germline fragment usage and junctional characteristics.According to the rearrangement of each gene, it was divided into positive and negative groups, and then the clinical and biological characteristics were compared between different groups.Results ① There were 37 males(71.2%) among the 52 children,aged from 1.8 to 16 years , with a median of 8 years,and the median WBC was 140.5 (2.7-667.1) ×10⁹·L^-1. There were 38 cases of IR(73.1%), and 14 cases of HR(26.9%). The follow-up time was 1.2 to 171.7 months and the median follow-up time was 136.3 months. There were 38 cases(73.1%) of long-term complete remission, 10 cases(19.2%) of recurrence and 4 cases(7.7%) of death from other cases. ②The incidence of TCRB, TCRG, TCRD and IgH clonal gene rearrangement was 85%, 85%, 38% and 21%, respectively. Ninety-four percent of the children were detected at least one gene rearrangement, and 88% of the children were at least examined two gene rearrangements. The TCRB, TCRD, TCRG, and IgH rearrangements were dominated by complete V_β-(D_β)-J_β, V_δ-J_δ, V_γI-J_γ1.3/2.3, and D_H-J_H incomplete rearrangement, respectively. Different combinations of germline gene segments resulted in the combinatorial diversity, and the deletion and random insertion of nucleotides at the junction sites created an enormous junctional diversity. ③Among the ten relapsed children, six were compared the Ig/TCR gene rearrangement pattern between diagnosis and recurrence,and four patients had recurrence of Ig/TCR gene rearrangement pattern at the time of initial diagnosis and two patients changed. ④The positive rates of SIL-TAL1 fusion gene were 0 in 11 patients with positive IgH rearrangement and 34.1% (14/41) in 41 children with negative IgH rearrangement,P=0.025 . ⑤The high-risk ratio of TCRB gene rearrangement positive group (20.5%, 9/44) was lower than that of negative group (62.5%, 5/8), P=0.025. The remission rate at the 33rd day of the TCRB or TCRG gene rearrangement positive group (89.4%, 42/44) was higher than that of the negative group (10.6%, 5/8), P=0.022, and the ratio of MRD level ≥10^-3on the 78th day (10.8%, 4/37) was lower than the negative group (50.0%, 3/6), P=0.045.Conclusion The usage of germline fragments of clonal Ig/TCR gene rearrangements and the DNA sequence of their junction regions were diverse, which was helpful for further screening of MRD markers of T-ALL in children.

Key words: Childhood T-cell acute lymphoblastic leukemia, Gene rearrangement, Immunoglobulin, T cell receptor

王婵娟, 崔蕾, 李伟京, 赵晓曦, 高超, 吴敏媛, 王天有, 李志刚. Ig/TCR基因重排在儿童急性T淋巴细胞白血病中的表达模式特点[J]. 中国循证儿科杂志, 2019, 14(2): 106-111.

WANG Chan-juan, CUI Lei, LI Wei-jing, ZHAO Xiao-xi, GAO Chao, WU Min-yuan, WANG Tian-you, Li Zhi-gang. The characteristics of Ig/TCR gene rearrangement patterns in childhood T-cell acute lymphoblastic leukemia[J]. Chinese Journal of Evidence -Based Pediatric, 2019, 14(2): 106-111.

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