Yoshimi Akihide, Kurokawa Mineo
Nihon Rinsho. 2014 Jun;72(6):1012-7.
The introduction of next generation sequencing technology has greatly broadened our view on the genetic landscape of hematological malignancies. The first comprehensive experiment of acute myeloid leukemia(AML) using genome-wide analysis has also shed light on the clonal evolution of AML, which seems to have been underestimated. It is now possible to precisely define clonal size and selection at different stages. This approach demonstrated that AML at diagnosis is either monoclonal or oligoclonal, harboring a selected number of genetically defined subclones. Furthermore, targeted deep sequencing of diagnosis and relapse pairs revealed that founding clones or subclones present at diagnosis obtain some additional mutations that contribute to clonal expansion and/or chemoresistance. Some subclones may be eradicated by treatment, whereas others are resistant to chemotherapeutic agents and ultimately grow out. The molecular heterogeneity in AML will have a great impact on the development of targeted therapies.
下一代测序技术的引入极大地拓宽了我们对血液系统恶性肿瘤基因格局的认识。首次使用全基因组分析对急性髓系白血病（AML）进行的全面实验也揭示了AML的克隆进化，而这一点似乎一直被低估。现在能够精确界定不同阶段的克隆大小和选择情况。该方法表明，诊断时的AML要么是单克隆的，要么是寡克隆的，含有一定数量经过基因定义的亚克隆。此外，对诊断和复发配对样本进行靶向深度测序发现，诊断时存在的起始克隆或亚克隆会获得一些额外的突变，这些突变有助于克隆扩增和/或产生化疗耐药性。一些亚克隆可能会被治疗清除，而其他亚克隆则对化疗药物耐药并最终发展壮大。AML中的分子异质性将对靶向治疗的发展产生重大影响。
