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

Duggan, JM;Buechler, MB;Olson, RM;Hohl, TM;Hamerman, JA;

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/EBP 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.