Myeloid progenitor cluster formation drives emergency and leukemic myelopoiesis

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