Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia.
Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia.
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DOI：
10.1126/science.1164266
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发表时间：
2008-11-28
期刊：
影响因子：
--
通讯作者：
Downing JR
中科院分区：
文献类型：
--
作者：
Mullighan CG;Phillips LA;Su X;Ma J;Miller CB;Shurtleff SA;Downing JR
大多数儿童急性淋巴细胞性白血病(ALL)是可以治愈的，但对于一小部分复发的患者来说，预后很差。为了探讨复发的遗传学基础，我们对61例ALL患者的匹配诊断和复发样本进行了全基因组DNA拷贝数分析。在大多数病例中，诊断和复发样本表现出不同的基因组拷贝数异常(CNA)模式，复发时获得的异常优先影响参与细胞周期调节和B细胞发育的基因。虽然诊断和复发样本是遗传相关的，但大多数复发样本缺乏诊断时存在的一些CNA，这表明导致复发的细胞是原代白血病细胞的祖先。回溯研究表明，在诊断时，与复发克隆相对应的细胞通常作为次要亚群存在。这些数据表明，导致所有复发的基因组异常是在治疗过程中选择的，受这些获得性改变影响的信号通路可能是治疗干预的合理靶点。
Most children with acute lymphoblastic leukemia (ALL) can be cured, but for the subset of patients who undergo relapse prognosis is dismal. To explore the genetic basis of relapse, we performed genome-wide DNA copy number analyses on matched diagnosis and relapse samples from 61 patients with ALL. In the majority of cases, the diagnosis and relapse samples showed different patterns of genomic copy number abnormalities (CNAs), with the abnormalities acquired at relapse preferentially affecting genes involved in cell cycle regulation and B cell development. Although the diagnosis and relapse samples were genetically related, most relapse samples lacked some of the CNAs present at diagnosis, suggesting that the cells responsible for relapse are ancestral to the primary leukemia cells. Backtracking studies demonstrated that cells corresponding to relapse clone were often present as minor sub-populations at diagnosis. These data suggest that genomic abnormalities contributing to ALL relapse are selected for during treatment and that the signaling pathways affected by these acquired alterations may be rational targets for therapeutic intervention.
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