Aberrant mast-cell differentiation in mice lacking the stem-cell leukemia gene

The stem cell leukemia (SCL) gene encodes a basic helix-loop-helix transcription factor expressed in erythroid, megakaryocyte, and mast-cell lineages. SCL is essential for growth of megakaryocyte and erythroid progenitors. We have used a conditional knockout of SCL (SCL-/Delta) to examine its function in mast cells, critical effectors of the immune system. SCL-/Delta mice had markedly increased numbers of mast-cell progenitors (MCPs) within the peritoneal fluid, bone marrow, and spleen. Fractionation of bone marrow myeloid progenitors demonstrated that these MCPs were present in the megakaryocyte-erythroid-restricted cell fraction. In contrast, unilineage MCPs from control mice were present in the cell fraction with granulocyte-macrophage potential. The aberrant mast-cell differentiation of SCL-/Delta megakaryocyte-erythroid progenitors was associated with increased expression of GATA-2. Despite increased numbers of MCPs in SCL-/Delta mice, numbers of mature tissue mast cells were not increased unless SCL-/Delta mice were treated with IL-3 and stem-cell factor. In part, this may be due to a requirement for SCL in normal mast-cell maturation: SCL-/A mast cells had reduced expression of the high-affinity IgE receptor and mast cell proteases, MCP-5 and MCP-6. Together, these studies suggest that loss of SCL leads to aberrant mast-cell differentiation of megakaryocyte-erythroid progenitors.