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Myeloid progenitor cluster formation drives emergency and leukaemic myelopoiesis

Hrault, A;Binnewies, M;Leong, S;Calero-Nieto, FJ;Zhang, SY;Kang, YA;Wang, X;Pietras, EM;Chu, SH;Barry-Holson, K;Armstrong, S;Gttgens, B;Passegu, E;

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-1, G-CSF, TGF and CXCL4) and activation of an inducible Irf8 and -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.