BCR-ABL融合基因ABL激酶区突变对慢性髓系白血病酪酸激酶抑制剂(TKI)耐药的研究

Study on the resistance of BCR-ABL fusion gene ABL kinase region mutation to chronic myeloid leukemia tyrosine kinase inhibitor (TKI)

目的:探讨BCR-ABL融合基因ABL激酶区突变对慢性髓系白血病(chronic myelogenous leukemia, CML)酪酸激酶抑制剂(Tyrosine kinase inhibitors, TKI)耐药的影响。方法:随机抽取于我院就诊的60例接受伊马替尼治疗的CML患者为研究对象,采用巢式RT-PCR对患者骨髓液BCR-ABL mRNA内ABL激酶区序列进行逆转录扩增和测序,进行同源性比较分析ABL激酶区突变,并分析其与伊马替尼耐药的关系。结果:(1)60例CML患者中发生21例ABL激酶区突变,共检测出22种点突变共38次,CML患者发生ABL激酶区突变的阳性率35.00%;60例患者中共发生耐药19例,伊马替尼治疗CML患者的总耐药率为31.67%(19/60),伊马替尼治疗CML患者发生突变后的耐药率为90.48%(19/21)。(2)分层研究中CML慢性期、加速期、急变期患者的突变率和耐药率分别为16.67%(3/18)、33.33%(1/3)、30.77%(8/26)、100.00%(8/8)、62.50%(10/16),100.00%(10/10)。各疾病时期患者的突变率和耐药率比较有统计学意义(P<0.05)。结论:伊马替尼治疗CML患者容易引起ABL激酶区突变,导致患者耐药。ABL激酶区突变存在突变位点广泛,性质多样等特点,且与疾病进展情况有明显关联。

Objective:To investigate the effect of BCR-ABL fusion gene ABL kinase mutation on the resistance of chronic myelogenous leukemia(CML) to tyrosine kinase inhibitors(TKI). Methods:60 hospitalized patients with CML who were treated with imatinib were randomly chosen as the subjects. Nested RT-PCR was used to reverse-transcribe and sequence the ABL kinase region of BCR-ABL mRNA in bone marrow fluid. The ABL kinase region mutation was analyzed by homology, with its drug resistance to imatinib analyzed. Results:(1) A total of 21 ABL kinase mutations occurred in 60 CML patients. A total of 22 point mutations were detected 38 times. The positive rate of ABL kinase mutations in CML patients was 35.00 %;20 out of 60 patients developed resistance. The total drug resistance rate of imatinib in patients with CML was 31.67 %(19/60), and the resistance rate after mutation in imatinib-treated CML patients was 90.48 %(19/21).(2)The mutation rate and the drug resistance rate of patients with chronic, accelerated and blast crisis in CML were 16.67 %(3/18), 33.33 %(1/3), 30.77 %(8/26), 100.00 %(8/8), 62.50 %(10/16) and 100.00 %(10/10) respectively. The mutation rate and the drug resistance rate of patients in each disease period were statistically significant(P<0.05). Conclusion:Imatinib in patients with CML is prone to cause mutations in the ABL kinase domain, leading to drug resistance in patients. ABL kinase region mutations have a wide range of mutation sites and diverse properties, and are significantly associated with disease progression.