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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Cohort Studies
-
Histones / genetics
-
Histones / metabolism
-
Humans
-
Kidney / metabolism
-
Kidney Neoplasms / genetics*
-
Kidney Neoplasms / metabolism
-
Mutation
-
Neoplasm Proteins / chemistry
-
Neoplasm Proteins / genetics*
-
Neoplasm Proteins / metabolism
-
Nuclear Proteins / chemistry
-
Nuclear Proteins / genetics*
-
Nuclear Proteins / metabolism
-
Protein Binding
-
Protein Structure, Tertiary
-
Proto-Oncogene Proteins c-myc / genetics
-
Proto-Oncogene Proteins c-myc / metabolism
-
Transcription Factors / chemistry
-
Transcription Factors / genetics*
-
Transcription Factors / metabolism
-
Wilms Tumor / genetics*
-
Wilms Tumor / metabolism
Substances
-
Histones
-
MLLT1 protein, human
-
MYC protein, human
-
Neoplasm Proteins
-
Nuclear Proteins
-
Proto-Oncogene Proteins c-myc
-
Transcription Factors