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(-/Delta) 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.
Salmon
Jessica M
JM
Rotary Bone Marrow Research Laboratories, Royal Melbourne Hospital, Melbourne, Australia.
Slater
Nicholas J
NJ
Hall
Mark A
MA
McCormack
Matthew P
MP
Nutt
Stephen L
SL
Jane
Stephen M
SM
Curtis
David J
DJ
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D041905:Erythroid Cells / Q000166:cytology; D050989:GATA2 Transcription Factor / Q000235:genetics; D006801:Humans; D007938:Leukemia / Q000235:genetics; D008264:Macrophages / Q000166:cytology; D008407:Mast Cells / Q000166:cytology* / Q000473:pathology; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D013234:Stem Cells / Q000166:cytology; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014162:Transfection; D015854:Up-Regulation
D051792:Basic Helix-Loop-Helix Proteins; D050989:GATA2 Transcription Factor; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C494712:Gata2 protein, mouse; C489366:Tal1 protein, mouse