Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.
N Engl J Med. 2012 Mar 22;366(12):1090-8. doi: 10.1056/NEJMoa1106968. Epub 2012 Mar 14.
The myelodysplastic syndromes are a group of hematologic disorders that often evolve into secondary acute myeloid leukemia (AML). The genetic changes that underlie progression from the myelodysplastic syndromes to secondary AML are not well understood.
We performed whole-genome sequencing of seven paired samples of skin and bone marrow in seven subjects with secondary AML to identify somatic mutations specific to secondary AML. We then genotyped a bone marrow sample obtained during the antecedent myelodysplastic-syndrome stage from each subject to determine the presence or absence of the specific somatic mutations. We identified recurrent mutations in coding genes and defined the clonal architecture of each pair of samples from the myelodysplastic-syndrome stage and the secondary-AML stage, using the allele burden of hundreds of mutations.
Approximately 85% of bone marrow cells were clonal in the myelodysplastic-syndrome and secondary-AML samples, regardless of the myeloblast count. The secondary-AML samples contained mutations in 11 recurrently mutated genes, including 4 genes that have not been previously implicated in the myelodysplastic syndromes or AML. In every case, progression to acute leukemia was defined by the persistence of an antecedent founding clone containing 182 to 660 somatic mutations and the outgrowth or emergence of at least one subclone, harboring dozens to hundreds of new mutations. All founding clones and subclones contained at least one mutation in a coding gene.
Nearly all the bone marrow cells in patients with myelodysplastic syndromes and secondary AML are clonally derived. Genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection. Recurrent gene mutations are found in both founding clones and daughter subclones. (Funded by the National Institutes of Health and others.).
骨髓增生异常综合征是一组血液疾病，常发展为继发性急性髓系白血病（AML）。导致骨髓增生异常综合征向继发性 AML 进展的遗传变化尚不清楚。
我们对 7 例继发性 AML 患者的 7 对皮肤和骨髓样本进行了全基因组测序，以鉴定特异性继发性 AML 的体细胞突变。然后，我们对每位患者在骨髓增生异常综合征阶段获得的骨髓样本进行基因分型，以确定特定体细胞突变的存在与否。我们在编码基因中发现了复发性突变，并使用数百个突变的等位基因负担来定义从骨髓增生异常综合征阶段和继发性 AML 阶段的每一对样本的克隆结构。
无论原始细胞计数如何，骨髓增生异常综合征和继发性 AML 样本中约 85%的骨髓细胞均为克隆性。继发性 AML 样本中包含 11 个复发性突变基因的突变，包括 4 个以前未涉及骨髓增生异常综合征或 AML 的基因。在每种情况下，急性白血病的进展都通过包含 182 至 660 个体细胞突变的前体细胞克隆的持续存在以及至少一个亚克隆的生长或出现来定义，该亚克隆含有数十至数百个新突变。所有起始克隆和亚克隆均包含编码基因中的至少一个突变。
骨髓增生异常综合征和继发性 AML 患者的几乎所有骨髓细胞均为克隆性来源。继发性 AML 的遗传进化是一个动态过程，由多次突变获得和克隆选择塑造。在起始克隆和子克隆中都发现了复发性基因突变。（由美国国立卫生研究院等资助）。
