Neuroblastoma is composed of two super-enhancer-associated differentiation states

Tim Van Groningen, Jan Koster, Linda J. Valentijn, Danny A. Zwijnenburg, Nurdan Akogul, Nancy E. Hasselt, Marloes Broekmans, Franciska Haneveld, Natalia E. Nowakowska, Johannes Bras, Carel J.M. Van Noesel, Aldo Jongejan, Antoine H. Van Kampen, Linda Koster, Frank Baas, Lianne Van Dijk-Kerkhoven, Margriet Huizer-Smit, Maria C. Lecca, Alvin Chan, Arjan LakemanPiet Molenaar, Richard Volckmann, Ellen M. Westerhout, Mohamed Hamdi, Peter G. Van Sluis, Marli E. Ebus, Jan J. Molenaar, Godelieve A. Tytgat, Bart A. Westerman, Johan Van Nes*, Rogier Versteeg

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1261-1266
Number of pages6
JournalNature Genetics
Volume49
Issue number8
DOIs
Publication statusPublished - 1 Aug 2017

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