Abstract

Although many aspects of blood production are well understood, the spatial organization of myeloid differentiation in the bone marrow remains unknown. Here we use imaging to track granulocyte/macrophage progenitor (GMP) behaviour in mice during emergency and leukaemic myelopoiesis. In the steady state, we find individual GMPs scattered throughout the bone marrow. During regeneration, we observe expanding GMP patches forming defined GMP clusters, which, in turn, locally differentiate into granulocytes. The timed release of important bone marrow niche signals (SCF, IL-1β, G-CSF, TGFβ and CXCL4) and activation of an inducible Irf8 and β-catenin progenitor self-renewal network control the transient formation of regenerating GMP clusters. In leukaemia, we show that GMP clusters are constantly produced owing to persistent activation of the self-renewal network and a lack of termination cytokines that normally restore haematopoietic stem-cell quiescence. Our results uncover a previously unrecognized dynamic behaviour of GMPs in situ, which tunes emergency myelopoiesis and is hijacked in leukaemia.

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Acknowledgements

We thank A. Leavitt (UCSF) for providing G-CSF; P. Frenette for advice on imaging approaches and the gift of Clxl4-cre:iDTR mice; M. Kissner and M. Lee for management of our Flow Cytometry core facility; and all members of the Passegué laboratory for critical insights and suggestions. This work was supported by NIH K01DK098315 award to E.M.P.; a Bloodwise and CRUK program grants and Wellcome Trust funding to the Cambridge Stem Cell Institute to B.G.; and NIH R01HL092471, R01HL111266 and P30DK063720 grants, Rita Allen Scholar Award and Leukemia Lymphoma Society Scholar Award to E.P.

Author information

Author notes

    • Aurélie Hérault
    • , Mikhail Binnewies
    •  & Stephanie Leong

    These authors contributed equally to this work.

    • Emmanuelle Passegué

    Present address: Columbia Stem Cell Initiative, Department of Genetics and Development, Columbia University Medical Center, New York, New York 10032, USA.

Affiliations

  1. The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California 94143, USA

    • Aurélie Hérault
    • , Mikhail Binnewies
    • , Stephanie Leong
    • , Si Yi Zhang
    • , Yoon-A Kang
    • , Eric M. Pietras
    • , Keegan Barry-Holson
    •  & Emmanuelle Passegué
  2. Cambridge University Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust and MRC Cambridge Stem Cell Institute, Hills Road, Cambridge CB2 0XY, UK

    • Fernando J. Calero-Nieto
    • , Xiaonan Wang
    •  & Berthold Göttgens
  3. Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA

    • S. Haihua Chu
    •  & Scott Armstrong

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Contributions

A.H., M.B. and S.L. performed all of the experiments with help from S.Y.Z. for dragon bead assays, Y.-A.K. for β-catenin studies, E.M.P. for IL-1 experiments, F.J.C.-N., X.W. and B.G. for Fluidigm and single-cell RNA-seq analyses, and S.H.C. and S.A. for MLL/AF9 experiments. K.B.-H. initiated the imaging studies. A.H., M.B. and S.L. designed the experiments and interpreted the results. A.H. and E.P. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Emmanuelle Passegué.

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https://doi.org/10.1038/nature21693

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