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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

278 Scopus citations

Abstract

Somatic mutations in te t 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.

Original languageEnglish (US)
Pages (from-to)580-584
Number of pages5
JournalNature
Volume557
Issue number7706
DOIs
StatePublished - May 24 2018

ASJC Scopus subject areas

  • General

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