论文部分内容阅读
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 patients with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL) often have a short course of recurrence and are prone to mutations in the ABL kinase domain following treatment with tyrosine kinase inhibitors (TKIs). In order to further study the characteristics of easy relapse after treatment with TKI in patients with Ph + ALL, ABL kinase mutation in 35 patients with TKI-resistant Ph + ALL was detected by direct sequencing. The results showed that there were ABL kinase mutations in 77.1% (27/35) patients, of which T315I mutation accounted for 55.6% of patients with ABL kinase mutations, especially for the first time found that G: C → A: T mutation Ph + ALL patients accounted for the total ABL kinase 77.8% (21/27) of the regionally mutated Ph + ALL patients, including T315I, E255K and E459K. Second, chromosomes of 8 patients with two or more ABL kinase mutations in Ph + ALL were all complex karyotypes, and 5 chromosomes were diagnosed as TKI-resistant Ph + ALL with complicated karyotype by newly diagnosed t (9; 22) (P <0.05). However, there was a mutation in the ABL kinase domain. Moreover, the expression level of uracil-N-glycosylase 2 (UNG2) in the resistant Ph + ALL group was significantly lower than that in the newly diagnosed group UNG2 deletion in the nucleus increases the chance of a G: C → A: T mutation. Conclusion: The Chinese population of TKI resistant Ph + ALL has a high proportion of ABL kinase G: C → A: T mutations and a high degree of genomic instability. Low expression of UNG2 in resistant Ph + ALL patients may be one of the factors of G: C → A: T mutation in high proportion of ABL kinase in patients with drug-resistant Ph + ALL.