Myeloid progenitor cluster formation drives emergency and leukaemic myelopoiesis

Aurélie Hérault, Mikhail Binnewies, Stephanie Leong, Fernando J. Calero-Nieto, Si Yi Zhang, Yoon-A Kang, Xiaonan Wang, Eric M. Pietras, S. Haihua Chu, Keegan Barry-Holson, Scott Armstrong, Berthold Göttgens and Emmanuelle Passegué ()
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Aurélie Hérault: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco
Mikhail Binnewies: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco
Stephanie Leong: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco
Fernando J. Calero-Nieto: Cambridge Institute for Medical Research, Wellcome Trust and MRC Cambridge Stem Cell Institute
Si Yi Zhang: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco
Yoon-A Kang: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco
Xiaonan Wang: Cambridge Institute for Medical Research, Wellcome Trust and MRC Cambridge Stem Cell Institute
Eric M. Pietras: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco
S. Haihua Chu: Dana-Farber Cancer Institute, Boston Children’s Hospital, Harvard Medical School
Keegan Barry-Holson: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco
Scott Armstrong: Dana-Farber Cancer Institute, Boston Children’s Hospital, Harvard Medical School
Berthold Göttgens: Cambridge Institute for Medical Research, Wellcome Trust and MRC Cambridge Stem Cell Institute
Emmanuelle Passegué: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco

Nature, 2017, vol. 544, issue 7648, 53-58

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature21693

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