Single-cell genotyping demonstrates complex clonal diversity in acute myeloid leukemia.
Single-cell genotyping demonstrates complex clonal diversity in acute myeloid leukemia.
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单细胞基因分型证明了急性髓系白血病复杂的克隆多样性。
DOI：
10.1126/scitranslmed.aaa0763
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发表时间：
2015-04-01
影响因子：
17.1
通讯作者：
Radich JP
中科院分区：
文献类型：
--
作者：
Paguirigan AL;Smith J;Meshinchi S;Carroll M;Maley C;Radich JP
癌症中的克隆进化-在进展和治疗过程中选择和出现越来越恶性的克隆，导致癌症转移和复发-已被强调为白血病和其他癌症生物学中的重要现象。跟踪突变等位基因，以确定从诊断到复发或原发部位到转移的克隆性，以灵敏和定量的方式最常使用下一代测序进行。这样的方法通过使用一组假设外推来自大量肿瘤样品的宏基因组的DNA的测序数据中的等位基因频率来确定克隆频率。通常采用的计算框架假设特定的模式，在单细胞中获得独特的突变事件和突变的杂合性的顺序。然而，这些假设对于急性髓性白血病（AML）样本中的所有突变位点都不准确。为了评估单个AML样本中的克隆多样性的当前模型是否适合于常见突变，我们开发了直接对AML单细胞进行基因分型的方案。单细胞分析表明，FLT 3和NPM 1的突变发生在纯合和杂合状态，分布在至少9个不同的克隆群体中的所有样品分析。对于在不同位点含有突变的细胞，似乎存在趋同进化和差异进化轨迹。这项工作表明，潜在的肿瘤异质性超出了目前在AML中的理解，这可能是重要的治疗方法，以消除白血病细胞负荷和控制克隆进化诱导的复发的发展。
Clonal evolution in cancer – the selection for and emergence of increasingly malignant clones during progression and therapy, resulting in cancer metastasis and relapse – has been highlighted as an important phenomenon in the biology of leukemia and other cancers. Tracking mutant alleles to determine clonality from diagnosis to relapse, or primary site to metastases, in a sensitive and quantitative manner is most often performed using next generation sequencing. Such methods determine clonal frequencies by extrapolation of allele frequencies in sequencing data of DNA from the metagenome of bulk tumor samples using a set of assumptions. The computational framework that is usually employed assumes specific patterns in the order of acquisition of unique mutational events and heterozygosity of mutations in single cells. However, these assumptions are not accurate for all mutant loci in acute myeloid leukemia (AML) samples. In order to assess whether current models of clonal diversity within individual AML samples are appropriate for common mutations, we developed protocols to directly genotype AML single cells. Single cell analysis demonstrates that mutations of FLT3 and NPM1 occur in both homozygous and heterozygous states, distributed among at least 9 distinct clonal populations in all samples analyzed. There appears to be convergent evolution and differential evolutionary trajectories for cells containing mutations at different loci. This work suggests an underlying tumor heterogeneity beyond what is currently understood in AML, which may be important in the development of therapeutic approaches to eliminate leukemic cell burden and control clonal evolution-induced relapse.
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影响因子：
64.5
作者：
Welch JS;Ley TJ;Link DC;Miller CA;Larson DE;Koboldt DC;Wartman LD;Lamprecht TL;Liu F;Xia J;Kandoth C;Fulton RS;McLellan MD;Dooling DJ;Wallis JW;Chen K;Harris CC;Schmidt HK;Kalicki-Veizer JM;Lu C;Zhang Q;Lin L;O'Laughlin MD;McMichael JF;Delehaunty KD;Fulton LA;Magrini VJ;McGrath SD;Demeter RT;Vickery TL;Hundal J;Cook LL;Swift GW;Reed JP;Alldredge PA;Wylie TN;Walker JR;Watson MA;Heath SE;Shannon WD;Varghese N;Nagarajan R;Payton JE;Baty JD;Kulkarni S;Klco JM;Tomasson MH;Westervelt P;Walter MJ;Graubert TA;DiPersio JF;Ding L;Mardis ER;Wilson RK
通讯作者：
Wilson RK
影响因子：
64.8
作者：
Greaves, Mel;Maley, Carlo C.
通讯作者：
Maley, Carlo C.
影响因子：
20.3
作者：
Thiede, C;Steudel, C;Illmer, T
通讯作者：
Illmer, T
影响因子：
8
作者：
Jan M;Majeti R
通讯作者：
Majeti R
影响因子：
20.3
作者：
Keats, Jonathan J.;Chesi, Marta;Bergsagel, P. Leif
通讯作者：
Bergsagel, P. Leif