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

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

Author information

1
Department of Medicine, University of Chicago, Chicago, IL, USA.
2
Committee on Immunology, University of Chicago, Chicago, IL, USA.
3
Department of Genetics, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
4
Department of Biochemistry, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
5
Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA.
6
Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
7
Translational Cell Genetics, Department for Pharmacology and Genetics, Medical University of Innsbruck, Innsbruck, Austria.
8
Research Centre, Hôpital Maisonneuve-Rosemont, Montreal, Quebec, Canada.
9
Department of Pathology and Pediatrics, University of Chicago, Chicago, IL, USA.
10
Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
11
Marine Biological Laboratory, Woods Hole, MA, USA.
12
Hematology Division, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montreal, Quebec, Canada.
13
Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
14
Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
15
Department of Medicine, University of Chicago, Chicago, IL, USA. bjabri@bsd.uchicago.edu.
16
Committee on Immunology, University of Chicago, Chicago, IL, USA. bjabri@bsd.uchicago.edu.
17
Department of Pathology and Pediatrics, University of Chicago, Chicago, IL, USA. bjabri@bsd.uchicago.edu.

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.

PMID:
29769727
PMCID:
PMC6238954
DOI:
10.1038/s41586-018-0125-z
[Indexed for MEDLINE]
Free PMC Article

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