| First Author | Meisel M | Year | 2018 |
| Journal | Nature | Volume | 557 |
| Issue | 7706 | Pages | 580-584 |
| PubMed ID | 29769727 | Mgi Jnum | J:262415 |
| Mgi Id | MGI:6159206 | Doi | 10.1038/s41586-018-0125-z |
| Citation | Meisel M, et al. (2018) Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature 557(7706):580-584 |
| abstractText | 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. |
