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. Musch, Glaucia 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 and Bana Jabri ()
Additional contact information
Marlies Meisel: University of Chicago
Reinhard Hinterleitner: University of Chicago
Alain Pacis: CHU Sainte-Justine Research Center
Li Chen: University of Chicago
Zachary M. Earley: University of Chicago
Toufic Mayassi: University of Chicago
Joseph F. Pierre: University of Chicago
Jordan D. Ernest: University of Chicago
Heather J. Galipeau: McMaster University
Nikolaus Thuille: Medical University of Innsbruck
Romain Bouziat: University of Chicago
Manuel Buscarlet: Hôpital Maisonneuve-Rosemont
Daina L. Ringus: University of Chicago
Yitang Wang: University of Chicago
Ye Li: University of Chicago
Vu Dinh: University of Chicago
Sangman M. Kim: University of Chicago
Benjamin D. McDonald: University of Chicago
Matthew A. Zurenski: University of Chicago
Mark W. Musch: University of Chicago
Glaucia C. Furtado: Icahn School of Medicine at Mount Sinai
Sergio A. Lira: Icahn School of Medicine at Mount Sinai
Gottfried Baier: Medical University of Innsbruck
Eugene B. Chang: University of Chicago
A. Murat Eren: University of Chicago
Christopher R. Weber: University of Chicago
Lambert Busque: Hôpital Maisonneuve-Rosemont
Lucy A. Godley: University of Chicago
Elena F. Verdú: McMaster University
Luis B. Barreiro: CHU Sainte-Justine Research Center
Bana Jabri: University of Chicago

Nature, 2018, vol. 557, issue 7706, 580-584

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41586-018-0125-z

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