Acute loss of TET function results in aggressive myeloid cancer in mice

Nat Commun. 2015 Nov 26;6:10071. doi: 10.1038/ncomms10071.

Abstract

TET-family dioxygenases oxidize 5-methylcytosine (5mC) in DNA, and exert tumour suppressor activity in many types of cancers. Even in the absence of TET coding region mutations, TET loss-of-function is strongly associated with cancer. Here we show that acute elimination of TET function induces the rapid development of an aggressive, fully-penetrant and cell-autonomous myeloid leukaemia in mice, pointing to a causative role for TET loss-of-function in this myeloid malignancy. Phenotypic and transcriptional profiling shows aberrant differentiation of haematopoietic stem/progenitor cells, impaired erythroid and lymphoid differentiation and strong skewing to the myeloid lineage, with only a mild relation to changes in DNA modification. We also observe progressive accumulation of phospho-H2AX and strong impairment of DNA damage repair pathways, suggesting a key role for TET proteins in maintaining genome integrity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA Repair / genetics
  • DNA-Binding Proteins / genetics*
  • Dioxygenases
  • Hematopoietic Stem Cells / metabolism*
  • Histones / metabolism
  • Leukemia, Myeloid / genetics*
  • Leukemia, Myeloid / pathology
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Proto-Oncogene Proteins / genetics*
  • RNA, Messenger / metabolism*
  • Tumor Stem Cell Assay

Substances

  • DNA-Binding Proteins
  • Histones
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Tet2 protein, mouse
  • Dioxygenases
  • Tet3 protein, mouse

Associated data

  • GEO/GSE72630