Lavrov Alexander V, Ustaeva Oksana A, Adilgereeva Elmira P, Smirnikhina Svetlana A, Chelysheva Ekaterina Y, Shukhov Oleg A, Shatokhin Yuriy V, Mordanov Sergey V, Turkina Anna G, Kutsev Sergey I
Laboratory of Mutagenesis, Federal State Budgetary Institution Research Centre for Medical Genetics, Moscow, Russian Federation.
Department of Molecular and Cellular Genetics, State Budgetary Educational Institution of Higher Professional Education Russian National Research Medical University named after N.I. Pirogov of Ministry of Health of the Russian Federation, Moscow, Russian Federation.
PLoS One. 2017 Sep 13;12(9):e0182901. doi: 10.1371/journal.pone.0182901. eCollection 2017.
Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the presence of BCR/ABL fusion gene in leukemic cells, which promotes uncontrolled cell proliferation. Up to 20% of CML patients show primary resistance or non-optimal response to tyrosine kinase inhibitor (TKI) therapy. We investigated the association between copy number variation (CNV) in glutathione S-transferases (GST) and cytochromes (CYP) and the response rate to TKI. We enrolled 47 patients with CML: 31 with an optimal response and 16 with failure at 6 months in accordance with European LeukemiaNet 2013 recommendations. CNV detection was performed using SALSA MLPA P128-C1 Cytochrome P450 probe mix. Patients with optimal response and with failure of TKI therapy showed different frequencies of wild type and mutated CYPs and GST (p<0.0013). Validation in the group of 15 patients proved high prognostic value (p = 0.02): positive and negative predictive value 83% and 78%; sensitivity and specificity 71% and 88%. Wild type genotypes of CYP and GST associate with a worse response to TKI treatment in CML patients. This test can be recommended for further clinical trials.
慢性髓性白血病（CML）是一种骨髓增殖性疾病，其特征是白血病细胞中存在BCR/ABL融合基因，该基因促进细胞不受控制地增殖。高达20%的CML患者对酪氨酸激酶抑制剂（TKI）治疗表现出原发性耐药或反应不佳。我们研究了谷胱甘肽S-转移酶（GST）和细胞色素（CYP）的拷贝数变异（CNV）与TKI反应率之间的关联。我们纳入了47例CML患者：根据欧洲白血病网络2013年的建议，31例反应良好，16例在6个月时治疗失败。使用SALSA MLPA P128-C1细胞色素P450探针混合物进行CNV检测。反应良好和TKI治疗失败的患者显示出野生型和突变型CYP和GST的频率不同（p<0.0013）。在15例患者组中的验证证明具有较高的预后价值（p = 0.02）：阳性和阴性预测值分别为83%和78%；敏感性和特异性分别为71%和88%。CYP和GST的野生型基因型与CML患者对TKI治疗的较差反应相关。该检测可推荐用于进一步的临床试验。
