Spectrum of somatic mutation dynamics in chronic myeloid leukemia following tyrosine kinase inhibitor therapy
Spectrum of somatic mutation dynamics in chronic myeloid leukemia following tyrosine kinase inhibitor therapy
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酪氨酸激酶抑制剂治疗后慢性粒细胞白血病的体细胞突变动态谱
DOI：
10.1182/blood-2016-04-708560
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发表时间：
2017-01-05
期刊：
影响因子：
20.3
通讯作者：
Kim, Dennis (Dong Hwan)
中科院分区：
文献类型：
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作者：
Kim, TaeHyung;Tyndel, Marc S.;Kim, Dennis (Dong Hwan)
体细胞突变通常在各种髓系肿瘤中检测到，但尚未在慢性髓系白血病（CML）中进行系统研究。我们对来自100名CML患者的总共300个系列样本进行了靶向深度测序; 37名患者携带突变。其中16个有证据表明突变来自白血病前克隆。使用无监督的层次聚类，我们确定了5种不同的模式，突变动力学酪氨酸激酶抑制剂（TKI）治疗后产生的。这项研究表明，突变的获得，持久性和清除模式各不相同，但与临床结果有许多有趣的相关性。尽管成功的TKI应答（模式1），突变负荷通常持续存在，这提供了间接证据表明这些突变也起源于白血病前突变，而表现出突变清除的患者（模式3）显示出混合的临床结局。不出所料，在治疗期间获得新突变的患者TKI治疗失败（模式2）。这些模式表明TKI治疗后CML突变动力学与其他髓系肿瘤明显不同。总之，CML中突变谱和动力学的临床意义应谨慎解释。
Somatic mutations commonly detected in a variety of myeloid neoplasms have not been systematically investigated in chronic myeloid leukemia (CML). We performed targeted deep sequencing on a total of 300 serial samples from 100 CML patients; 37 patients carried mutations. Sixteen of these had evidence of mutations originating from preleukemic clones. Using unsupervised hierarchical clustering, we identified 5 distinct patterns of mutation dynamics arising following tyrosine kinase inhibitor (TKI) therapy. This study demonstrates that patterns of mutation acquisition, persistence, and clearance vary but have a number of interesting correlations with clinical outcomes. Mutation burden often persisted despite successful TKI response (pattern 1), providing indirect evidence that these mutations also originated from preleukemic mutations, whereas patients exhibiting mutation clearance (pattern 3) showed mixed clinical outcomes. Unsurprisingly, patients acquiring new mutations during treatment failed TKI therapy (pattern 2). These patterns show that CML mutation dynamics following TKI therapy are markedly distinct from other myeloid neoplasms. In summary, clinical implications of mutation profiles and dynamics in CML should be interpreted with caution.