Myeloid progenitor cluster formation drives emergency and leukaemic myelopoiesis

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. During emergency myelopoiesis in mice, clusters of self-renewing granulocyte/macrophage progenitors (GMP) are transiently formed in the bone marrow cavity to produce a burst of myeloid cells; in leukaemia, GMP clusters persist and constantly generate myeloid leukaemia cells. Bone marrow's emergency blood bank During haematogenesis in the bone marrow, granulocyte/macrophage progenitors (GMPs) give rise to more differentiated granulocytes. Aurélie Hérault et al . now find that, during emergency blood generation, GMP clusters of self-renewing cells are formed, which give rise to more differentiated cells, timed through secretion of cytokines. However, during leukaemogenesis, these clusters persist and supply a constant generation of leukaemia cells. These findings provide new insights into the dynamic behaviour of GMPs.