ABL激酶区突变的检测与伊马替尼耐药  

Characteristics of ABL kinase domain mutations in BCR-ABL mRNA and imainib resistance

作　　者：崔亚娟[1] 王光平[1] 徐嘉鹰 信红亚[1] 袁小瑜[1] 

机构地区：[1]中南大学湘雅医院血液科,长沙410013 [2]上海华冠生物芯片有限公司,上海200100

出　　处：《中南药学》2013年第3期161-165,共5页Central South Pharmacy

摘　　要：目的研究慢性粒细胞白血病(chronic myeloid leukemia,CML)患者ABL酪氨酸激酶区突变及伊马替尼耐药。方法用巢式RT-PCR对35例CML患者骨髓液BCR-ABL mRNA内ABL激酶区序列进行逆转录、扩增,测序和同源性比较分析ABL激酶区突变,并分析其伊马替尼耐药。结果 35例患者检出突变16例,阳性率45.71%。CML慢性期、加速期、急变期患者突变率分别为47.83%(11/23)、50%(1/2)和40%(4/10),其差异无显著性(P=0.858);16例突变患者中,共检出26种点突变,包括Y253H、T315I、F317L、M351T、L387F、A380D、H396R、G398R、D455G、E459K和1例185 bp碱基缺失突变等。其中A269V、D274G、S286G、V299M、C305Y、R307W、G312R、I314V、L324Q、K356E、D381G、K403E、K419E、L471P、A474T和S485P突变暂未见文献报道,可能为新的突变。在这些新发现的突变中,D274G、S286G、C305Y和K356E等突变可能与伊马替尼(imatinib,IM)治疗抗性有关。结论约半数患者存在ABL激酶区突变,突变位点广泛,性质多样,既存在单一位点突变,也可多位点同时存在,突变的发生与年龄、性别无关,部分突变与伊马替尼耐药有关。ABL基因激酶区突变检测有助于酪氨酸激酶抑制剂疗效的评估、治疗方案的调整。Objective To explore the mutation characteristics in ABL tyrosine kinase domain of BCR-ABL mRNA and imainib resistance in chronic myeloid leukemia （CML） patients. Methods Nested reverse transcriptase-polymerase chain reaction （RT-PCR） was used to transcript and amplify the ABL kinase domain of BCR-ABL mRNA, and the product was used to directly sequence. Imatinib resistance was assessed by the clinical manifestation and laboratory tests. Results In the 35 patients analyzed, mutations in the ABL kinase domain were detected in 16 patients （45.71%）. The mutation rate in chronic phase, accelerated phase and blast phase of the patients with CML was 47.83% （11/23）, 50% （1/2） and 40% （4/10）, respectively, in which there was no significant difference among these 3 phases. Twenty-six types of mutations distributed in 16 patients, including Y253H, T315I, F317L, M351T, L387F, A380D, H396R, G398R, D455G, E459K and 185 bp deletion and so on. Mutations ofA269V, D274G, S286G, V299M, C305Y, R307W, G312R, I314V, L324Q, K356E, D381G, K403E, K419E, L471P, A474T and S485P have not been reported so far. Clinical information indicated that the novel mutations of D274G, S286G, C305Y and K356E may be related to imatinib resistance. Conclusion Mutations ofABL kinase domain in BCR-ABL exist in half of the patients, and a variety of mutations are detected in the whole ABL kinase domain. Analysis of the mutation in ABL kinase domain of the BCR-ABL is helpful for the assessment of efficacy and therapeutic strategy adjust- ment for tyrosine kinase inhibitor to treat CML patients.

关 键 词：ABL酪氨酸激酶 突变 酪氨酸酶抑制剂 慢性粒细胞白血病 耐药 

分 类 号：R733.3[医药卫生—肿瘤] R969[医药卫生—临床医学]