Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Nature (London), 2018-05, Vol.557 (7706), p.580-584

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2018

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Somatic mutations in tet methylcytosine dioxygenase 2 (TET2), which encodes an epigenetic modifier enzyme, drive the development of haematopoietic malignancies . 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 . However, pre-leukaemic myeloproliferation (PMP) occurs in only a fraction of Tet2 mice and humans with TET2 mutations , 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.