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 F. 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. Musch; Glaucia 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

doi:10.1038/s41586-018-0125-z

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 F. 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^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

314 Scopus citations

Abstract

Somatic mutations in te t 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.

Original language	English (US)
Pages (from-to)	580-584
Number of pages	5
Journal	Nature
Volume	557
Issue number	7706
DOIs	https://doi.org/10.1038/s41586-018-0125-z
State	Published - May 24 2018

Funding

Acknowledgements We thank the University of Chicago DNA Sequencing Core facility for assistance with sequencing; the Calcul Québec and Compute Canada for providing access to the supercomputer Briaree from the University of Montreal; the Histology Core facility at the University of Chicago Human Tissue Resource Center for assistance with histology; S. Hwang (University of Chicago) for providing LysM-Cre mice; and V. Abadie (Université de Montréal) for discussions and critical reading of the manuscript. This work was supported by grants from the Cancer Center Support Grant P30CA014599 to B.J.; Digestive Diseases Research Core Center P30DK42086 at the University of Chicago to R.H., E.B.C., C.R.W. and B.J.; P01DK072201, R01DK110352 and 5R01CA161373 to S.A.L. and G.C.F.; F32 DK105728-01A1 to J.F.P.; CCFA Research Fellowship Award (ID: 480735) to M.M.; FWF Austrian Science Fund (P30324-B21) and Christian Doppler Society (I-CARE) to G.B.; and by a CIHR grant MOP (#20003029), a Canada Research Chair to E.F.V. and a Canada Research Chair to L.B.B. A.P. was supported by a fellowship from FRQS.

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Meisel, M., Hinterleitner, R., Pacis, A., Chen, L., Earley, Z. M., Mayassi, T., Pierre, J. F., Ernest, J. D., Galipeau, H. J., Thuille, N., Bouziat, R., Buscarlet, M., Ringus, D. L., Wang, Y., Li, Y., DInh, V., Kim, S. M., McDonald, B. D., Zurenski, M. A., ... 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

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title = "Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2018 Macmillan Publishers Ltd., part of Springer Nature.",

year = "2018",

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doi = "10.1038/s41586-018-0125-z",

language = "English (US)",

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Meisel, M, Hinterleitner, R, Pacis, A, Chen, L, Earley, ZM, Mayassi, T, Pierre, JF, 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

TY - JOUR

T1 - Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host

AU - Meisel, Marlies

AU - Hinterleitner, Reinhard

AU - Pacis, Alain

AU - Chen, Li

AU - Earley, Zachary M.

AU - Mayassi, Toufic

AU - Pierre, Joseph F.

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

PY - 2018/5/24

Y1 - 2018/5/24

N2 - 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.

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

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