Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host

Nature. 2018 May;557(7706):580-584. doi: 10.1038/s41586-018-0125-z. Epub 2018 May 16.

Abstract

Somatic mutations in tet methylcytosine dioxygenase 2 (TET2), which encodes an epigenetic modifier enzyme, drive the development of haematopoietic malignancies1-7. In both humans and mice, TET2 deficiency leads to increased self-renewal of haematopoietic stem cells with a net developmental bias towards the myeloid lineage1,4,8,9. However, pre-leukaemic myeloproliferation (PMP) occurs in only a fraction of Tet2-/- mice8,9 and humans with TET2 mutations1,3,5-7, suggesting that extrinsic non-cell-autonomous factors are required for disease onset. Here we show that bacterial translocation and increased interleukin-6 production, resulting from dysfunction of the small-intestinal barrier, are critical for the development of PMP in mice that lack Tet2 expression in haematopoietic cells. Furthermore, in symptom-free Tet2-/- mice, PMP can be induced by disrupting intestinal barrier integrity, or in response to systemic bacterial stimuli such as the toll-like receptor 2 agonist. PMP was reversed by antibiotic treatment and failed to develop in germ-free Tet2-/- mice, which illustrates the importance of microbial signals in the development of this condition. Our findings demonstrate the requirement for microbial-dependent inflammation in the development of PMP and provide a mechanistic basis for the variation in PMP penetrance observed in Tet2-/- mice. This study will prompt new lines of investigation that may profoundly affect the prevention and management of haematopoietic malignancies.

Publication types

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

MeSH terms

  • Animals
  • Asymptomatic Diseases*
  • Bacterial Infections / immunology
  • Bacterial Infections / microbiology
  • Bacterial Physiological Phenomena* / immunology
  • Cell Proliferation*
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / genetics
  • Female
  • Germ-Free Life
  • Inflammation / microbiology
  • Interleukin-6 / immunology
  • Intestinal Mucosa / metabolism
  • Lactobacillus / chemistry
  • Lactobacillus / cytology
  • Lactobacillus / immunology
  • Leukemia / microbiology*
  • Leukemia / pathology*
  • Male
  • Mice
  • Penetrance
  • Permeability
  • Proto-Oncogene Proteins / deficiency*
  • Proto-Oncogene Proteins / genetics
  • Toll-Like Receptor 2 / agonists

Substances

  • DNA-Binding Proteins
  • Interleukin-6
  • Proto-Oncogene Proteins
  • Tet2 protein, mouse
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2