title: BCAP inhibits proliferation and differentiation of myeloid progenitors in the steady state and during demand situations.
abstract: B-cell adaptor for phosphatidylinositol 3-kinase (BCAP) is a signaling adaptor expressed in mature hematopoietic cells, including monocytes and neutrophils. Here we investigated the role of BCAP in the homeostasis and development of these myeloid lineages. BCAP-/-mice had more bone marrow (BM) monocytes than wild-type (WT) mice, and in mixed WT:BCAP-/-BM chimeras, monocytes and neutrophils skewed toward BCAP-/-origin, showing a competitive advantage for BCAP-/-myeloid cells. BCAP was expressed in BM hematopoietic progenitors, including lineage-Sca-1+c-kit+(LSK), common myeloid progenitor, and granulocyte/macrophage progenitor (GMP) cells. At the steady state, BCAP-/-GMP cells expressed more IRF8 and less C/EBPα than did WT GMP cells, which correlated with an increase in monocyte progenitors and a decrease in granulocyte progenitors among GMP cells. Strikingly, BCAP-/-progenitors proliferated and produced more myeloid cells of both neutrophil and monocyte/macrophage lineages than did WT progenitors in myeloid colony-forming unit assays, supporting a cell-intrinsic role of BCAP in inhibiting myeloid proliferation and differentiation. Consistent with these findings, during cyclophosphamide-induced myeloablation or specific monocyte depletion, BCAP-/-mice replenished circulating monocytes and neutrophils earlier than WT mice. During myeloid replenishment after cyclophosphamide-induced myeloablation, BCAP-/-mice had increased LSK proliferation and increased numbers of LSK and GMP cells compared with WT mice. Furthermore, BCAP-/-mice accumulated more monocytes and neutrophils in the spleen than did WT mice duringListeria monocytogenesinfection. Together, these data identify BCAP as a novel inhibitor of myelopoiesis in the steady state and of emergency myelopoiesis during demand conditions.
authors.affiliation: Immunology Program, Benaroya Research Institute, Seattle, WA.|Department of Immunology, University of Washington, Seattle, WA; and.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Duggan
authors.affiliation: Immunology Program, Benaroya Research Institute, Seattle, WA.|Department of Immunology, University of Washington, Seattle, WA; and.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Buechler
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA; and.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Olson
authors.affiliation: Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Hohl
authors.affiliation: Immunology Program, Benaroya Research Institute, Seattle, WA.|Department of Immunology, University of Washington, Seattle, WA; and.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Hamerman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D006706:Homeostasis; D051379:Mice; D009000:Monocytes / Q000166:cytology; D023461:Myeloid Progenitor Cells / Q000166:cytology*; D038042:Myelopoiesis; D009504:Neutrophils / Q000166:cytology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C487978:Pik3ap1 protein, mouse