中国人群耐药Ph阳性急性淋巴细胞白血病高比例ABL激酶区G∶C→A∶T突变和尿嘧啶-N-糖基化酶异常表达研究  

Frequently ABL Kinase Domain G:C→A:T Mutation and Uracil DNA Glycosylase Abnormal Expression in TKI-resistant Acute Lymphoblastic Leukemia of Chinese Population

作　　者：沈宏杰[1] 陈子兴[1] 何军[1] 岑建农[1] 邱桥成[1] 丁子轩[1] 姚利[1] 陈艳[1] 陈苏宁[1] 薛永权[1] 

机构地区：[1]苏州大学附属第一医院江苏省血液研究所、卫生部血栓与止血重点实验室,江苏苏州215006

出　　处：《中国实验血液学杂志》2014年第4期889-893,共5页Journal of Experimental Hematology

基　　金：江苏省临床医学科技专项(BL2012005);江苏省临床医学中心(ZX201102);江苏省高校优势学科建设工程(PAPD);苏州市科技发展计划(SYSD2011075);苏州市科技基础设施建设计划项目(SZS201001)

摘　　要：大多数费城染色体阳性急性淋巴细胞白血病(Ph+ALL)患者在使用酪氨酸激酶抑制剂(TKI)治疗后常表现为复发时间短及易出现ABL激酶区突变现象。为进一步研究Ph+ALL患者使用TKI治疗后易复发特点,本研究采用直接测序法检测了35例TKI耐药Ph+ALL患者ABL激酶区突变。结果发现,77.1%(27/35)患者存在ABL激酶区突变,其中T315I突变患者占ABL激酶区突变患者55.6%,特别是首次发现G:C→A:T突变Ph+ALL患者占总ABL激酶区突变Ph+ALL患者77.8%(21/27),包括T315I、E255K和E459K。其次,8例具有两种或两种以上ABL激酶区突变Ph+ALL患者染色体均为复杂核型,5例染色体由初诊单纯t(9;22)进展为复杂核型的TKI耐药Ph+ALL均出现ABL激酶区突变;并且,尿嘧啶-N-糖基化酶2(UNG2)在耐药Ph+ALL组中转录水平表达显著低于初诊组,具有统计学差异(P<0.05),而细胞核内UNG2缺失能增加G:C→A:T突变几率。结论:中国人群TKI耐药Ph+ALL具有高比例ABL激酶区G:C→A:T突变和高度基因组不稳定性。耐药Ph+ALL患者低表达UNG2可能是耐药Ph+ALL患者发生高比例ABL激酶区G:C→A:T突变的因素之一。Most Philadelphia chromosome-positive acute lymphoblastic leukemia （Ph → ALL） patients often show rapid recurrence and development of ABL kinase domain （KD） mutation after tyrosine kinase inhibitor （TKI） treatment. To further investigate the mechanism of Ph＋ ALL fast relapse after TKI treatment, ABL KD mutation in 35 Chinese Ph → ALL with TKI resistance was detected by direct sequencing. The results showed that 77.1% （27/35） Ph ＋ ALL patients with TKI resistance had ABL KD mutation and 55.6% （ 15/27 ） Ph＋ ALL patients with ABL KD mutation had T315L Interestingly, 77.8 % （ 21/27 ） Ph＋ ALL showed ABL mutation G. C→ A： T, including T3151, E255K and E459K. Furthermore, all the Ph＋ ALL patients with two or more ABL KD mutations collaborated with complex chromosome abnormality and all the TKI-resistant Ph＋ ALL patients, whose karyotype progressed from simple t（9;22） into complex, developed ABL KD mutation. Moreover, the expression level of uracil-DNA glycosylase UNG2, which inhibits G： C→A：T transition in genomic DNA, decreased in Ph＋ ALL with TKI-resistance compared to that in newly diagnosis Ph＋ ALL. It is concluded that there is a high frequent ABL KD G： C→A： T mutation and a high genomic instability in Chinese TKI-resistant Ph＋ ALL. In addition, the decreased UNG2 expression in TKI-resistant Ph＋ ALL probably contributes to their high rate of ABL KD G：C→A：T mutation.

关 键 词：中国人群 急性淋巴细胞白血病 ABL激酶区 DNA突变分析 尿嘧啶-N-糖基化酶 

分 类 号：R733.71[医药卫生—肿瘤]