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目的探讨伊马替尼治疗慢性粒细胞白血病(CML)患者ABL酪氨酸激酶区点突变的发生情况及临床意义。方法采用巢式PCR扩增23例CML患者不同时期的40份骨髓标本的ABL激酶区,对扩增产物纯化、双向测序并进行序列同源性比对。结果7人(30.43%)检测出点突变,共导致5种类型的氨基酸替换:T315I3例,Y253H、E255K、F317L及G321W各1例。慢性期、加速期和急变期患者点突变的例数分别为2例、2例和3例。其中6例患者测序前经400mg/d伊马替尼治疗无效,加大伊马替尼剂量至(600～800)mg/d,随访3～6个月,仅F317L患者获得部分细胞遗传学缓解,另外5例患者均无遗传学反应,且Y253H和1例T315I疾病进展至急变期。G321W为初治慢性期患者,经400mg/d伊马替尼治疗达到完全血液学缓解,BCR-ABL+细胞比例显著下降。结论ABL激酶区点突变是CML患者对伊马替尼耐药的重要原因。不同类型的突变导致的耐药程度不完全相同,且并非所有点突变都会导致耐药的发生。监测ABL激酶区点突变有助于预测疗效并及早调整治疗。
Objective To investigate the occurrence and clinical significance of ABL tyrosine kinase site mutations in patients with chronic myeloid leukemia (CML) treated with imatinib. Methods The nested PCR was used to amplify the ABL kinase region of 40 bone marrow specimens of 23 patients with CML at different stages. The amplified products were purified by two-way sequencing and sequence homology comparison. Results Seven mutations (30.43%) detected five kinds of amino acid substitutions: T315I3, Y253H, E255K, F317L and G321W, respectively. The number of cases of point mutations in patients with chronic phase, accelerated phase and acute phase were 2 cases, 2 cases and 3 cases respectively. Six patients were ineffective with 400 mg / d imatinib prior to sequencing, with imatinib dose increasing to (600-800) mg / d, followed by 3-6 months, and only partial cytogenetic response was obtained in patients with F317L , And the other 5 patients had no genetic response, and Y253H and 1 T315I disease progressed to the blastic phase. G321W was initially treated in patients with chronic phase, after 400mg / d imatinib treatment to achieve complete hematological response, BCR-ABL + cells decreased significantly. Conclusions Point mutation in ABL kinase is an important reason for resistance to imatinib in CML patients. Different types of mutations lead to different degrees of resistance, and not all point mutations lead to drug resistance. Monitoring point mutations in the ABL kinase region can help predict the efficacy and adjust treatment as soon as possible.