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 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. MuschGlaucia 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, Bana Jabri

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Somatic mutations in te t 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.

Original languageEnglish (US)
Pages (from-to)580-584
Number of pages5
JournalNature
Volume557
Issue number7706
DOIs
StatePublished - May 24 2018

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Dioxygenases
Bacterial Translocation
Toll-Like Receptor 2
Penetrance
Hematologic Neoplasms
Hematopoietic Stem Cells
Epigenomics
Interleukin-6
Anti-Bacterial Agents
Inflammation
Mutation
Enzymes

All Science Journal Classification (ASJC) codes

  • General

Cite this

Meisel, M., Hinterleitner, R., Pacis, A., Chen, L., Earley, Z. M., Mayassi, T., ... Jabri, B. (2018). Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature, 557(7706), 580-584. https://doi.org/10.1038/s41586-018-0125-z

Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. / Meisel, Marlies; Hinterleitner, Reinhard; Pacis, Alain; Chen, Li; Earley, Zachary M.; Mayassi, Toufic; Pierre, Joseph; 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.

In: Nature, Vol. 557, No. 7706, 24.05.2018, p. 580-584.

Research output: Contribution to journalArticle

Meisel, M, Hinterleitner, R, Pacis, A, Chen, L, Earley, ZM, Mayassi, T, Pierre, J, Ernest, JD, Galipeau, HJ, Thuille, N, Bouziat, R, Buscarlet, M, Ringus, DL, Wang, Y, Li, Y, DInh, V, Kim, SM, McDonald, BD, Zurenski, MA, Musch, MW, Furtado, GC, Lira, SA, Baier, G, Chang, EB, Eren, AM, Weber, CR, Busque, L, Godley, LA, Verdú, EF, Barreiro, LB & Jabri, B 2018, 'Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host', Nature, vol. 557, no. 7706, pp. 580-584. https://doi.org/10.1038/s41586-018-0125-z
Meisel M, Hinterleitner R, Pacis A, Chen L, Earley ZM, Mayassi T et al. Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature. 2018 May 24;557(7706):580-584. https://doi.org/10.1038/s41586-018-0125-z
Meisel, Marlies ; Hinterleitner, Reinhard ; Pacis, Alain ; Chen, Li ; Earley, Zachary M. ; Mayassi, Toufic ; Pierre, Joseph ; 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. / Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. In: Nature. 2018 ; Vol. 557, No. 7706. pp. 580-584.
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abstract = "Somatic mutations in te t 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.",
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AU - Meisel, Marlies

AU - Hinterleitner, Reinhard

AU - Pacis, Alain

AU - Chen, Li

AU - Earley, Zachary M.

AU - Mayassi, Toufic

AU - Pierre, Joseph

AU - Ernest, Jordan D.

AU - Galipeau, Heather J.

AU - Thuille, Nikolaus

AU - Bouziat, Romain

AU - Buscarlet, Manuel

AU - Ringus, Daina L.

AU - Wang, Yitang

AU - Li, Ye

AU - DInh, Vu

AU - Kim, Sangman M.

AU - McDonald, Benjamin D.

AU - Zurenski, Matthew A.

AU - Musch, Mark W.

AU - Furtado, Glaucia C.

AU - Lira, Sergio A.

AU - Baier, Gottfried

AU - Chang, Eugene B.

AU - Eren, A. Murat

AU - Weber, Christopher R.

AU - Busque, Lambert

AU - Godley, Lucy A.

AU - Verdú, Elena F.

AU - Barreiro, Luis B.

AU - Jabri, Bana

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