Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host Academic Article uri icon

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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.

authors

  • Meisel, Marlies
  • Hinterleitner, Reinhard
  • Pacis, Alain
  • Chen, Li
  • Earley, Zachary M
  • Mayassi, Toufic
  • Pierre, Joseph F
  • Ernest, Jordan D
  • Galipeau, Heather J
  • Thuille, Nikolaus
  • Bouziat, Romain
  • Buscarlet, Manuel
  • Ringus, Daina L
  • Wang, Yitang
  • Li, Ye
  • Dinh, Vu
  • Kim, Sangman M
  • McDonald, Benjamin D
  • Zurenski, Matthew A
  • Musch, Mark W
  • Furtado, Glaucia C
  • Lira, Sergio A
  • Baier, Gottfried
  • Chang, Eugene B
  • Eren, A Murat
  • Weber, Christopher R
  • Busque, Lambert
  • Godley, Lucy A
  • Verdu-Bercik, Elena
  • Barreiro, Luis B
  • Jabri, Bana

publication date

  • May 2018