Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia.
Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia.
复制标题
DOI：
10.1038/nm.4125
复制
发表时间：
2016-07
期刊：
影响因子：
82.9
通讯作者：
Mason CE
中科院分区：
文献类型：
--
作者：
Li S;Garrett-Bakelman FE;Chung SS;Sanders MA;Hricik T;Rapaport F;Patel J;Dillon R;Vijay P;Brown AL;Perl AE;Cannon J;Bullinger L;Luger S;Becker M;Lewis ID;To LB;Delwel R;Löwenberg B;Döhner H;Döhner K;Guzman ML;Hassane DC;Roboz GJ;Grimwade D;Valk PJ;D'Andrea RJ;Carroll M;Park CY;Neuberg D;Levine R;Melnick AM;Mason CE
遗传异质性影响大多数肿瘤的临床结果和进展。然而，对于表观遗传区室的等位基因多样性知之甚少，并且几乎没有关于急性髓性白血病（AML）的数据。在这里，我们通过在AML患者样本的四个CpGs（表观遗传等位基因）、体细胞突变和转录组中定义的基因组位点内的胞嘧啶甲基化来评估表观遗传异质性。我们观察到表观遗传等位基因负担与不良预后有关，并且在疾病进展过程中变化很大。表观遗传和遗传等位基因负担和模式遵循不同的模式和动力学在疾病进展。我们观察到在诊断时具有高外显等位基因和低体细胞突变负担的aml亚群，诊断时具有高体细胞突变和低外显等位基因负担的aml亚群，以及具有混合特征的aml亚群，这表明不同的肿瘤异质性模式。在肿瘤进展过程中，与启动子相关的外等位基因移位相关的基因表现出单细胞转录变异和差异表达的增加，表明对基因调控的功能影响。因此，遗传和表观遗传异质性可能以不同的动力学发生，每一种都可能影响肿瘤的生物学和临床特征。
Genetic heterogeneity contributes to clinical outcome and progression of most tumors. Yet, little is known regarding allelic diversity for epigenetic compartments and almost no data exists for acute myeloid leukemia (AML). Here we examined epigenetic heterogeneity as assessed by cytosine methylation within defined genomic loci with four CpGs (epigenetic alleles), somatic mutations and transcriptomes of AML patient samples at serial time points. We observe that epigenetic allele burden is linked to inferior outcome and varies considerably during disease progression. Epigenetic and genetic allelic burden and patterning follow different patterns and kinetics during disease progression. We observed a subset of AMLs with high epiallele and low somatic mutation burden at diagnosis, a subset with high somatic mutation and lower epiallele burdens at diagnosis, and a subset with a mixed profile, suggesting distinct modes of tumor heterogeneity. Genes linked to promoter-associated epiallele shifts during tumor progression display increased single-cell transcriptional variance and differential expression, suggesting functional impact on gene regulation. Thus, genetic and epigenetic heterogeneity can occur with distinct kinetics, each likely able to impact biological and clinical features of tumors.