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学科主题: 临床医学
题名:
我国210例伊马替尼耐药慢性髓细胞白血病和Ph阳性急性淋巴细胞白血病ABL1基因突变特征
其他题名: The characteristics of ABL1 gene mutations in 210 cases of Chinese patients who have imatinibresistant in chronic myeloid leukemia and Ph positive acute lymphoblastic leukemia
作者: 夏君燕1; 刘红星1; 王芳1; 朱娟1; 蔡鹏1; 童春容1; 朱平1
关键词: 伊马替尼 ; 耐药 ; 蛋白酪氨酸激酶类 ; 白血病,髓系,慢性,BCR-ABL阳性 ; 突变 ; Imatinib ; Drug resistance ; Protein-tyrosine kinases ; Leukemia,myelogenous,chronic,BCR-ABL positive ; Mutation
刊名: 中华检验医学杂志
发表日期: 2012
DOI: 10.3760/cma.j.issn.1009-9158.2012.01.006
卷: 35, 期:1, 页:17-22
收录类别: 中国科技核心期刊 ; 中文核心期刊 ; CSCD
文章类型: Journal Article
摘要: 目的 了解伊马替尼治疗后效果不佳的慢性髓细胞白血病(chronic myeloid leukemia,CML)及Ph阳性急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)患者BCR-ABL1激酶区突变(kinase domain mutation,KDM)的特征.方法 选取2007年9月至2010年12月北京市道培医院177例CML患者和33例Ph(+)ALL患者,均为我国患者.在患者治疗初期有效、后出现耐药时,或者治疗3个月以上疗效不佳时采集骨髓或外周血标本,共计243份.提取标本有核细胞中总RNA,反转录为cDNA.用巢式聚合酶链反应(polymerase chain reaction,PCR)扩增标本中BCR-ABL1融合基因的激酶区全长(第242~ 493位氨基酸的编码序列),使用AB3130XL型基因测序仪测定ABL1激酶区的基因序列,使用Variant Reporter V1.0软件分析基因突变结果.结果 共检测到32种ABL1基因不同种类的点突变,检出率为34.2%( 83/243).其中T315I占12% (10/83),检出的突变率最高;其余依次为Y253H占11% (9/83),G250E占7% (6/83),E255K占7% (6/83),M351T占6% (5/83),E459K占5% (4/83);Q252H、D276G、F317L、E355G、F359V、H396R均与4% (3/83).并发现了3例插入突变,2例为357-358insk,1例为V304RfsX17.在7例患者中发现同时存在2种以上的点突变.多种耐药突变可同时存在于1个克隆中,同一个体不仅有常见的耐药突变,也会出现少见的点突变、缺失突变、插入突变甚至导致激酶活性缺失的突变.结论 伊马替尼药物压力下白血病细胞的ABL1基因突变会随机出现,产生不同的耐药克隆;不同的耐药克隆可以在同一个体内并存.耐药克隆不仅有基因突变,还存在插入缺失突变. Objective To understand the characteristics of mutations in BCR-ABL1 kinase domain mutation,these chronic myeloid leukemia (CML) and Ph positive acute lymphoblastic leukemia (ALL)patients who got imatinib treatment had poor effect.Methods Totally 177 CML patients and 33 Ph( + )ALL patients were selected at Beijing Dao-Pei Hospital from Sep.2007 to Dec.2010.All of them were Chinese patients.Totally 243 bone marrow or peripheral blood specimens were collected from the patients,who had early effect,then resistance emergenced,or for more than 3 months of poor efficacy.Extracted total RNA from the specimens' nuclear cells,reversed transcription to cDNA.Amplified the whole span of BCRABL1 fusion kinase gene by nest PCR (from 242 to 493 amino acid coding sequence),used the type AB3130XL gene sequencing instrument determinate the gene sequence of ABL1 kinase region and then used the Variant Reporter V1.0 software to analyze the results of gene mutations.Results Thirty-two kinds of different mutations were detected of ABL1 gene mutations,accounting for 34.2% (83/243 cases).Among them,the T315I was 12% (10/83),mutation rate was the highest,followed by Y253H was 11% (9/83),G250E was 7% (6/83),E255K was 7% (6/83),M351T was 6% (5/83),E459K was 5% (4/83) ;Q252H,D276G,F317L,E355G,F359V,H396R were all 4% (3/83).Three cases of insertion mutations were found,including 2 cases of 357-358insk,1 case of V304RfsX17.Seven patients had found existence two or more point mutations.The multiple drug resistance mutations might exist in the same leukemia clone.The same individual was not only contain common resistance mutations,but also rare point mutations,insertion mutations.The mutations might be lead to loss of kinase activity.Conclusions Under the imatinib drugs pressure,the ABL1 gene mutation in leukemia cells appears randomly,and results in different resistant clones.Different resistant clones can coexist in the same patients in vivo; resistant clones not only contain point mutations,but also contain inserted deletion mutations.
语种: 中文
原文出处: 查看原文
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内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/49555
Appears in Collections:北京大学第一临床医学院_期刊论文

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作者单位: 1.100034,北京大学第一医院血液研究室
2.北京市道培医院检验中心

Recommended Citation:
夏君燕,刘红星,王芳,等. 我国210例伊马替尼耐药慢性髓细胞白血病和Ph阳性急性淋巴细胞白血病ABL1基因突变特征[J]. 中华检验医学杂志,2012,35(1):17-22.
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