Yao Yong-Gang, Ogasawara Yoji, Kajigaya Sachiko, Molldrem Jeffrey J, Falcão Roberto P, Pintão Maria-Carolina, McCoy J Philip, Rizzatti Edgar Gil, Young Neal S
Hematology Branch and Flow Cytometry Core Facility, National Heart, Lung, and Blood Institute, NIH Bldg 10 CRC, Rm 3E-5216, 10 Center Dr Bethesda, MD 20892, USA.
Blood. 2007 Jan 15;109(2):756-62. doi: 10.1182/blood-2006-01-011007. Epub 2006 Aug 31.
A high frequency of mtDNA somatic mutation has been observed in many tumors as well as in aging tissues. In this study, we analyzed the mtDNA control region sequence variation in 3534 single normal cells and individual blasts from 18 patients with leukemia and 10 healthy donors, to address the mutation process in leukemic cells. We found significant differences in mtDNA sequence, as represented by the number of haplotypes and the mean number of cells with each nonaggregate haplotype in a population of cells, in patients compared to controls. Patients with similar clinical leukemia types, particularly acute myeloid leukemia (AML), did not show a uniform pattern of sequence variation in single blasts. Some patients at relapse presented a complex shift of major haplotypes in single cells. Four patients showed high frequencies of cells containing mutations 189, 260, 16150, and 16488, respectively, as a result of clonal expansion and could be considered as potential markers for their respective disease progression. To our knowledge, this is the first large-scale study of mtDNA variation in single malignant cells. Our results suggest that the somatic mutation process in leukemia is complex, leading to diverse levels of genetic alterations due to either intrinsic aspects of leukemia pathophysiology or chemotherapy effects.
在许多肿瘤以及衰老组织中都观察到线粒体DNA（mtDNA）体细胞突变的高频率现象。在本研究中，我们分析了18例白血病患者和10名健康供体的3534个单个正常细胞及单个原始细胞中的mtDNA控制区序列变异，以探讨白血病细胞中的突变过程。我们发现，与对照组相比，患者的mtDNA序列存在显著差异，这种差异表现为单倍型数量以及细胞群体中每种非聚集单倍型的平均细胞数量。临床白血病类型相似的患者，尤其是急性髓系白血病（AML）患者，单个原始细胞中的序列变异模式并不一致。一些复发患者的单个细胞中主要单倍型出现了复杂的变化。4名患者由于克隆扩增，分别出现了含有189、260、16150和16488突变的高频率细胞，可被视为各自疾病进展的潜在标志物。据我们所知，这是首次对单个恶性细胞中的mtDNA变异进行大规模研究。我们的结果表明，白血病中的体细胞突变过程很复杂，由于白血病病理生理学的内在因素或化疗作用，导致了不同程度的基因改变。
