期刊
NATURE
卷 557, 期 7706, 页码 580-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-018-0125-z
关键词
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资金
- Cancer Center Support Grant [P30CA014599]
- Digestive Diseases Research Core Center at the University of Chicago [P30DK42086, P01DK072201, R01DK110352, 5R01CA161373, F32 DK105728-01A1]
- CCFA [480735]
- FWF Austrian Science Fund [P30324-B21]
- Christian Doppler Society (I-CARE)
- CIHR grant MOP [20003029]
- Canada Research Chair
- FRQS
- NATIONAL CANCER INSTITUTE [R01CA161373, P30CA014599] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [T32AI007090] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING [T32EB009412] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK110352, P01DK072201, R01DK067180, P30DK042086] Funding Source: NIH RePORTER
Somatic mutations in tet methylcytosine dioxygenase 2 (TET2), which encodes an epigenetic modifier enzyme, drive the development of haematopoietic malignancies(1-7). In both humans and mice, TET2 deficiency leads to increased self-renewal of haematopoietic stem cells with a net developmental bias towards the myeloid lineage(1,4,8,9). However, pre-leukaemic myeloproliferation (PMP) occurs in only a fraction of Tet2(-/-) mice(8,9) and humans with TET2 mutations(1,3,5-7), 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.
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