Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia
Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia
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DOI：
10.1016/s1535-6108(02)00096-x
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发表时间：
2002-08-01
期刊：
影响因子：
50.3
通讯作者：
Sawyers, CL
中科院分区：
文献类型：
--
作者：
Shah, NP;Nicoll, JM;Sawyers, CL
通过对慢性粒细胞白血病患者的血液或骨髓样本进行测序分析，我们在32例对酪氨酸激酶抑制剂伊马替尼初始应答后疾病复发的患者中，发现了29例患者的BCR-ABL激酶结构域突变。15个不同的氨基酸取代影响激酶结构域中的13个残基被发现。突变分为两组-那些改变直接接触伊马替尼的氨基酸和那些假定阻止BCR-ABL实现伊马替尼结合所需的非活性构象状态。不同的突变赋予不同程度的伊马替尼耐药。在稳定慢性期疾病患者亚组中检测到的突变与随后的疾病进展相关。在复发病例的一个子集中检测到多个独立的突变克隆。我们的数据支持预先存在的BCR-ABL突变赋予伊马替尼耐药的克隆选择模型。
Through sequencing analysis of blood or bone marrow samples from patients with chronic myeloid leukemia, we identified BCR-ABL kinase domain mutations in 29 of 32 patients whose disease relapsed after an initial response to the tyrosine kinase inhibitor imatinib. Fifteen different amino acid substitutions affecting 13 residues in the kinase domain were found. Mutations fell into two groups-those that alter amino acids that directly contact imatinib and those postulated to prevent BCR-ABL from achieving the inactive conformational state required for imatinib binding. Distinct mutations conferred varying degrees of imatinib resistance. Mutations detected in a subset of patients with stable chronic phase disease correlated with subsequent disease progression. Multiple independent mutant clones were detected in a subset of relapsed cases. Our data support a clonal selection model of preexisting BCR-ABL mutations that confer imatinib resistance.