Histone H3.3 mutations drive pediatric glioblastoma through upregulation of MYCN

Children and young adults with glioblastoma (GBM) have a median survival rate of only 12 to 15 months, and these GBMs are clinically and biologically distinct from histologically similar cancers in older adults. They are defined by highly specific mutations in the gene encoding the histone H3.3 variant H3F3A, occurring either at or close to key residues marked by methylation for regulation of transcription-K27 and G34. Here, we show that the cerebral hemisphere-specific G34 mutation drives a distinct expression signature through differential genomic binding of the K36 trimethylation mark (H3K36me3). The transcriptional program induced recapitulates that of the developing forebrain, and involves numerous markers of stem-cell maintenance, cell-fate decisions, and self-renewal. Critically, H3F3A G34 mutations cause profound upregulation of MYCN, a potent oncogene that is causative of GBMs when expressed in the correct developmental context. This driving aberration is selectively targetable in this patient population through inhibiting kinases responsible for stabilization of the protein.The authors acknowledge NHS funding to the National Institute for Health Research Biomedical Research Centre.This work is supported by Cancer Research UK, the Wellcome Trust, the Samantha Dickson Brain Tumour Trust, and The Stravros Niarchos Foundation

Scientific report 1996

CRC Beatson LaboratoriesSIGLEAvailable from British Library Document Supply Centre-DSC:8195.450(1996) / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Synthetic and spectral studies of potential anticancer drugs

SIGLEAvailable from British Library Document Supply Centre-DSC:DXN012564 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

The differential expression of genes in normal and neoplastic rat tissues

SIGLEAvailable from British Library Document Supply Centre- DSC:D40377/82 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

The differential expression of genes in normal and neoplastic rat tissues

SIGLEAvailable from British Library Document Supply Centre- DSC:D40377/82 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Human Retroviruses and AIDS. A compilation and analysis of nucleic acid and amino acid sequences: I--II; III--V

This compendium and the accompanying floppy diskettes are the result of an effort to compile and rapidly publish all relevant molecular data concerning the human immunodeficiency viruses (HIV) and related retroviruses. The scope of the compendium and database is best summarized by the five parts that it comprises: (I) HIV and SIV Nucleotide Sequences; (II) Amino Acid Sequences; (III) Analyses; (IV) Related Sequences; and (V) Database Communications. Information within all the parts is updated at least twice in each year, which accounts for the modes of binding and pagination in the compendium

Major components of the insulin-like growth factor axis are expressed early in chicken embryogenesis, with IGF binding protein (IGFBP)-5 expression subject to regulation by Sonic Hedgehog

Using whole-mount in situ hybridisation techniques, we have examined the expression of major components of the insulin-like growth factor (IGF) axis in early development of the chicken embryo, including both IGF-I and -II, the type 1 IGF receptor (IGFR), and two of the IGF binding proteins, (IGFBP)-2 and -5. We report that these genes fall into two distinct groups with respect to expression pattern, with IGFBP-2 displaying broad overlap of mRNA expression with IGFR and IGF-I during early development, whereas the expression profile of IGFBP-5 most closely resembled that of IGF-II. Comparison between different stages revealed IGFBP-2 mRNA was detected as early as stage 3, whereas I