title: Myeloid progenitor cluster formation drives emergency and leukaemic myelopoiesis.
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.
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Hérault
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Binnewies
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Leong
authors.affiliation: Cambridge University Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust and MRC Cambridge Stem Cell Institute, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Calero-Nieto
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Si Yi
authors.initials: SY
authors.lastname: Zhang
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Yoon-A
authors.initials: YA
authors.lastname: Kang
authors.affiliation: Cambridge University Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust and MRC Cambridge Stem Cell Institute, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Wang
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Pietras
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: S Haihua
authors.initials: SH
authors.lastname: Chu
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Keegan
authors.initials: K
authors.lastname: Barry-Holson
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Armstrong
authors.affiliation: Cambridge University Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust and MRC Cambridge Stem Cell Institute, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Passegué
mesh_terms: D000818:Animals; D000066673:Cell Self Renewal; D065150:Cellular Reprogramming; D016207:Cytokines / Q000378:metabolism; D055014:Granulocyte-Macrophage Progenitor Cells / Q000166:cytology* / Q000473:pathology*; D006098:Granulocytes / Q000166:cytology / Q000473:pathology; D050835:Interferon Regulatory Factors / Q000378:metabolism; D007938:Leukemia / Q000473:pathology*; D008264:Macrophages / Q000166:cytology / Q000473:pathology; D051379:Mice; D057054:Molecular Imaging; D038042:Myelopoiesis; D014411:Neoplastic Stem Cells / Q000473:pathology*; D055153:Stem Cell Niche / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism; D000099185:Interferon Regulatory Factor-8
chemical_list: D016207:Cytokines; D050835:Interferon Regulatory Factors; D051176:beta Catenin; D000099185:Interferon Regulatory Factor-8