BCAP inhibits myeloid cell development from hematopoietic progenitors.

Abstract

Abstract B cell adaptor for PI3-kinase (BCAP) is a signaling adaptor expressed in hematopoietic cells including macrophages, monocytes, and neutrophils. Here we asked if BCAP plays a role in development of these myeloid cells. We found that BCAP was expressed in bone marrow (BM) hematopoietic progenitors, including LSK (Lin−Sca1+cKit+), CMP (Common Myeloid Progenitor) and GMP (Granulocyte/Macrophage Progenitor) cells, suggesting that BCAP may impact myelopoiesis. BCAP−/− mice had more BM monocytes than WT mice, and in mixed chimeras generated with a 1:1 ratio of WT and BCAP−/− BM, monocytes and neutrophils in the BM, blood and spleen exhibited skewing towards BCAP−/− origin, showing a competitive advantage for BCAP−/− myeloid cells. Thus we hypothesized that BCAP inhibits myeloid development. Consistent with this hypothesis, BCAP-deficient BM LSK, CMP and GMP cells out-competed WT progenitors in mixed chimeras. In an in vitro myeloid colony-forming-unit assay, sorted BCAP−/− progenitors produced more myeloid cells than WT progenitors, supporting a cell-intrinsic role of BCAP in inhibiting myeloid differentiation. Furthermore, BCAP−/− progenitors were more mature than WT progenitors, indicating that BCAP−/− progenitors display accelerated myeloid development. During cyclophosphamide-induced myeloablation or specific monocyte depletion, BCAP−/− mice replenish circulating monocytes earlier than WT mice. Lastly, BCAP−/− progenitors showed increased expression of the myeloid-differentiating transcription factors IRF8 and C/EBPα compared to WT progenitors. Together, these data identify BCAP as an inhibitor of myeloid development from BM hematopoietic progenitors in the steady state and during demand conditions.