Forskning
Udskriv Udskriv
Switch language
Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet

EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

  1. Dysregulation of a long noncoding RNA reduces leptin leading to a leptin-responsive form of obesity

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Recurrent MET fusion genes represent a drug target in pediatric glioblastoma

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  5. FoxA1 directs the lineage and immunosuppressive properties of a novel regulatory T cell population in EAE and MS

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. The splicing factor RBM25 controls MYC activity in acute myeloid leukemia

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. BloodSpot: a database of healthy and malignant haematopoiesis updated with purified and single cell mRNA sequencing profiles

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Leukemogenic nucleophosmin mutation disrupts the transcription factor hub regulating granulo-monocytic fates

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Differences in Cell Cycle Status Underlie Transcriptional Heterogeneity in the HSC Compartment

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • Faizaan Mohammad
  • Simon Weissmann
  • Benjamin Leblanc
  • Deo P Pandey
  • Jonas W Højfeldt
  • Itys Comet
  • Chunqin Zheng
  • Jens Vilstrup Johansen
  • Nicolas Rapin
  • Bo T Porse
  • Andrey Tvardovskiy
  • Ole N Jensen
  • Nagore G Olaciregui
  • Cinzia Lavarino
  • Mariona Suñol
  • Carmen de Torres
  • Jaume Mora
  • Angel M Carcaboso
  • Kristian Helin
Vis graf over relationer

Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor that is located in the pons and primarily affects children. Nearly 80% of DIPGs harbor mutations in histone H3 genes, wherein lysine 27 is substituted with methionine (H3K27M). H3K27M has been shown to inhibit polycomb repressive complex 2 (PRC2), a multiprotein complex responsible for the methylation of H3 at lysine 27 (H3K27me), by binding to its catalytic subunit EZH2. Although DIPGs with the H3K27M mutation show global loss of H3K27me3, several genes retain H3K27me3. Here we describe a mouse model of DIPG in which H3K27M potentiates tumorigenesis. Using this model and primary patient-derived DIPG cell lines, we show that H3K27M-expressing tumors require PRC2 for proliferation. Furthermore, we demonstrate that small-molecule EZH2 inhibitors abolish tumor cell growth through a mechanism that is dependent on the induction of the tumor-suppressor protein p16INK4A. Genome-wide enrichment analyses show that the genes that retain H3K27me3 in H3K27M cells are strong polycomb targets. Furthermore, we find a highly significant overlap between genes that retain H3K27me3 in the DIPG mouse model and in human primary DIPGs expressing H3K27M. Taken together, these results show that residual PRC2 activity is required for the proliferation of H3K27M-expressing DIPGs, and that inhibition of EZH2 is a potential therapeutic strategy for the treatment of these tumors.

OriginalsprogEngelsk
TidsskriftNature Medicine
Vol/bind23
Udgave nummer4
Sider (fra-til)483-492
Antal sider10
ISSN1078-8956
DOI
StatusUdgivet - feb. 2017

ID: 52417422