Department of Oncogenomics, Academic Medical Center, Amsterdam, the Netherlands.
Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands.
Nat Genet. 2017 Aug;49(8):1261-1266. doi: 10.1038/ng.3899. Epub 2017 Jun 26.
Neuroblastoma and other pediatric tumors show a paucity of gene mutations, which has sparked an interest in their epigenetic regulation. Several tumor types include phenotypically divergent cells, resembling cells from different lineage development stages. It has been proposed that super-enhancer-associated transcription factor (TF) networks underlie lineage identity, but the role of these enhancers in intratumoral heterogeneity is unknown. Here we show that most neuroblastomas include two types of tumor cells with divergent gene expression profiles. Undifferentiated mesenchymal cells and committed adrenergic cells can interconvert and resemble cells from different lineage differentiation stages. ChIP-seq analysis of isogenic pairs of mesenchymal and adrenergic cells identified a distinct super-enhancer landscape and super-enhancer-associated TF network for each cell type. Expression of the mesenchymal TF PRRX1 could reprogram the super-enhancer and mRNA landscapes of adrenergic cells toward a mesenchymal state. Mesenchymal cells were more chemoresistant in vitro and were enriched in post-therapy and relapse tumors. Two super-enhancer-associated TF networks, which probably mediate lineage control in normal development, thus dominate epigenetic control of neuroblastoma and shape intratumoral heterogeneity.
神经母细胞瘤和其他儿科肿瘤表现出基因突变的缺乏，这激发了人们对其表观遗传调控的兴趣。几种肿瘤类型包括表型不同的细胞，类似于来自不同谱系发育阶段的细胞。有人提出，超级增强子相关转录因子（TF）网络是谱系身份的基础，但这些增强子在肿瘤内异质性中的作用尚不清楚。在这里，我们表明大多数神经母细胞瘤包括两种具有不同基因表达谱的肿瘤细胞。未分化的间充质细胞和有丝分裂的肾上腺素能细胞可以相互转化，并类似于来自不同谱系分化阶段的细胞。对间充质和肾上腺素能细胞的同基因对进行 ChIP-seq 分析，确定了每种细胞类型独特的超级增强子图谱和超级增强子相关 TF 网络。间充质 TF PRRX1 的表达可以重新编程肾上腺素能细胞的超级增强子和 mRNA 图谱，使其向间充质状态发展。间充质细胞在体外具有更强的耐药性，并且在治疗后和复发肿瘤中富集。两个超级增强子相关的 TF 网络，可能介导正常发育中的谱系控制，因此主导神经母细胞瘤的表观遗传控制，并塑造肿瘤内异质性。
