MLLT1 YEATS domain mutations in clinically distinctive Favourable Histology Wilms tumours

Elizabeth J. Perlman*, Samantha Gadd, Stefan T. Arold, Anand Radhakrishnan, Daniela S. Gerhard, Lawrence Jennings, Vicki Huff, Jaime M.Guidry Auvil, Tanja M. Davidsen, Jeffrey S. Dome, Daoud Meerzaman, Chih Hao Hsu, Cu Nguyen, James Anderson, Yussanne Ma, Andrew J. Mungall, Richard A. Moore, Marco A. Marra, Charles G. Mullighan, Jing MaDavid A. Wheeler, Oliver A. Hampton, Julie M. Gastier-Foster, Nicole Ross, Malcolm A. Smith

*Corresponding author for this work

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Wilms tumour is an embryonal tumour of childhood that closely resembles the developing kidney. Genomic changes responsible for the development of the majority of Wilms tumours remain largely unknown. Here we identify recurrent mutations within Wilms tumours that involve the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation during early development. The mutant MLLT1 protein shows altered binding to acetylated histone tails. Moreover, MLLT1-mutant tumours show an increase in MYC gene expression and HOX dysregulation. Patients with MLLT1-mutant tumours present at a younger age and have a high prevalence of precursor intralobar nephrogenic rests. These data support a model whereby activating MLLT1 mutations early in renal development result in the development of Wilms tumour.

Original languageEnglish (US)
Article number10013
JournalNature communications
Volume6
DOIs
StatePublished - Dec 4 2015

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Perlman, E. J., Gadd, S., Arold, S. T., Radhakrishnan, A., Gerhard, D. S., Jennings, L., Huff, V., Auvil, J. M. G., Davidsen, T. M., Dome, J. S., Meerzaman, D., Hsu, C. H., Nguyen, C., Anderson, J., Ma, Y., Mungall, A. J., Moore, R. A., Marra, M. A., Mullighan, C. G., ... Smith, M. A. (2015). MLLT1 YEATS domain mutations in clinically distinctive Favourable Histology Wilms tumours. Nature communications, 6, [10013]. https://doi.org/10.1038/ncomms10013