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BCAP inhibits proliferation and differentiation of myeloid progenitors in the steady state and during demand situations

Jeffrey M. Duggan, Matthew B. Buechler, Rebecca M. Olson, Tobias M. Hohl and Jessica A. Hamerman

Key Points

  • BCAP is expressed in hematopoietic stem and progenitor cells and inhibits myeloid cell development in a cell-intrinsic manner.

  • In the absence of BCAP, hematopoietic stem and progenitor cells are more proliferative, particularly in 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 lineageSca-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 during Listeria monocytogenes infection. Together, these data identify BCAP as a novel inhibitor of myelopoiesis in the steady state and of emergency myelopoiesis during demand conditions.

  • Submitted June 1, 2016.
  • Accepted January 7, 2017.
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