CYP3A5基因在急性白血病儿童中的表达及临床意义

Expression of CYP3A5 mRNA in children with acute leukemia

目的CYP3A5参与多种常用化疗药物的代谢反应。目前对于CYP3A5基因参与急性白血病的研究主要限于细胞系的体外研究。该文通过检测急性白血病患儿CYP3A5-6986位点的基因型分布特点和基因表达水平,探讨其基因表达水平对白血病患者治疗、预后评价的意义。方法①应用聚合酶链-限制性片段长度多态性方法(PCR-RFLP)及PCR产物序列测定,检测66例初治急性白血病患儿和20例对照儿童的CYP3A5-6986位点基因型分布;②实时定量PCR法检测病例组及对照组儿童骨髓单核细胞内wt-CYP3A5和SV1-CYP3A5 mRNA的表达水平。结果①对照组和急性白血病儿童CYP3A5-6986多态性位点存在野生型(CYP3A5*1/*1)、杂合突变型(CYP3A5*1/*3)、纯合突变型(CYP3A5*3/*3)3种基因型;②66例初治急性白血病患儿按基因型分组后对其mRNA表达水平进行检测,3组间的wt-CYP3A5 mRNA差异有显著性意义(P<0.05);③ALL组wt-CYP3A5 mRNA低表达者第1次化疗后的缓解率高于wt-CYP3A5 mRNA高表达者,两者比较差异有显著性意义(P<0.05);④对两例急性淋巴细胞性白血病患儿的CYP3A5 mRNA表达水平动态监测显示,1例复发前wt-CYP3A5 mRNA表达水平较缓解时升高。另1例wt-CYP3A5 mRNA表达一直处于较低水平,患儿目前仍处于缓解状态。结论wt-CYP3A5mRNA表达与白血病患儿的化疗疗效及预后密切相关,动态监测wt-CYP3A5 mRNA表达水平变化有助于判断病情变化。

Objective The cytochrome P450 subfamily ⅢA5 （ CYP3A5 ） gene is responsible for the metabolism of many clinically used anticancer agents. So far the studies on CYP3A5 gene has only been focused on the leukemia cell lines. This study examined the polymorphism of CYP3A5 and tried to find the possible relationship between CYP3A5 gene expression and treatment outcome or prognosis in children with acute leukemia. Methods The genotype distribution of CYP3A5-6986A/G gene polymorphism was detected with the polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP） method in 66 children with newly diagnosed acute leukemia （AL） and 22 control individuals. Quantitative real-time RT-PCR was used to examine wt-CYP3A5 and SV1-CYP3A5 mRNA levels in the bone marrow. Results Three genotypes of CYP3A5-6986A/G polymorphisms were found： CYP3A5 ＊ 1/＊ 1, CYP3A5 ＊ 1/＊ 3 and CYP3A5 ＊ 3/＊ 3. There were significant differences in the wt-CYP3A5 mRNA expression among the AL patients with different genotypes （ P 〈 0.05 ）. In patients with acute lymphocytic leukaemia （ ALL）, the complete remission （CR） rate in the group with a low expression of wt-CYP3A5 mRNA was significantly higher than that in the group with a high expression （P 〈 0.05）. A dynamic monitoring for wt-CYP3A5 mRNA expression was performed in two cases of ALL. The expression increased before ALL relapse compared with that in CR in a patient, while in the other patient, the expression was kept in a low level and the patient remained in CR. Conclusions wt-CYP3A5 mRNA expression was associated with the treatment outcome and prognosis in children with AL. Dynamic monitoring for wt-CYP3A5 mRNA expression in the bone marrow may be useful in the evaluation of the disease severity in childhood acute leukemia.