Myeloid progenitor cluster formation drives emergency and leukaemic myelopoiesis.
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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. |
Year of Publication | 2017
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Journal | Nature
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Volume | 544
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Issue | 7648
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Pages | 53-58
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Date Published | 2017 04 06
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ISSN | 1476-4687
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DOI | 10.1038/nature21693
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PubMed ID | 28355185
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PubMed Central ID | PMC5383507
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Grant list | R01 HL092471 / HL / NHLBI NIH HHS / United States
P30 DK063720 / DK / NIDDK NIH HHS / United States
K01 DK098315 / DK / NIDDK NIH HHS / United States
R01 HL111266 / HL / NHLBI NIH HHS / United States
Wellcome Trust / United Kingdom
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