Clonal architecture of secondary acute myeloid leukemia.
Clonal architecture of secondary acute myeloid leukemia.
复制标题
DOI：
10.1056/nejmoa1106968
复制
发表时间：
2012-03-22
期刊：
影响因子：
--
通讯作者：
Graubert TA
中科院分区：
文献类型：
--
作者：
Walter MJ;Shen D;Ding L;Shao J;Koboldt DC;Chen K;Larson DE;McLellan MD;Dooling D;Abbott R;Fulton R;Magrini V;Schmidt H;Kalicki-Veizer J;O'Laughlin M;Fan X;Grillot M;Witowski S;Heath S;Frater JL;Eades W;Tomasson M;Westervelt P;DiPersio JF;Link DC;Mardis ER;Ley TJ;Wilson RK;Graubert TA
骨髓增生异常综合征是一组血液系统疾病，通常会演变成继发性急性髓系白血病 (AML)。从骨髓增生异常综合征进展为继发性 AML 的基因变化尚不清楚。我们对七名继发性 AML 受试者的七对皮肤和骨髓样本进行了全基因组测序，以确定继发性 AML 特有的体细胞突变。然后，我们对每个受试者在先前的骨髓增生异常综合征阶段获得的骨髓样本进行基因分型，以确定是否存在特定的体细胞突变。我们利用数百个突变的等位基因负担，鉴定了编码基因中的反复突变，并定义了骨髓增生异常综合征阶段和继发性 AML 阶段的每对样本的克隆结构。无论成粒细胞计数如何，骨髓增生异常综合征和继发性 AML 样本中大约 85% 的骨髓细胞是克隆的。继发性 AML 样本包含 11 个反复突变基因的突变，其中包括 4 个之前未与骨髓增生异常综合征或 AML 相关的基因。在每种情况下，进展为急性白血病的定义是包含 182 至 660 个体细胞突变的先前创始克隆的持续存在，以及至少一个包含数十至数百个新突变的亚克隆的生长或出现。所有创始克隆和亚克隆的编码基因都至少含有一个突变。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都是克隆衍生的。继发性 AML 的遗传进化是一个由突变获取和克隆选择的多个周期形成的动态过程。在创始克隆和子代亚克隆中都发现了反复的基因突变。 （由美国国立卫生研究院和其他机构资助。）
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.)