title: Myeloid development is selectively disrupted in PU.1 null mice.
abstract: The ets family transcription factor PU.1 is expressed in monocytes/macrophages, neutrophils, mast cells, B cells, and early erythroblasts, but not in T cells. We have recently shown that PU.1 gene disruption results in mice with no detectable monocytes/macrophages and B cells but T-cell development is retained. Although neutrophil development occurred in these mice, it was delayed and markedly reduced. We now proceed to demonstrate that PU. 1 null hematopoietic cells fail to proliferate or form colonies in response to macrophage colony-stimulating factor (M-CSF), granulocyte CSF (G-CSF), and granulocyte/macrophage CSF (GM-CSF). In contrast, PU.1 null cells did proliferate and form colonies in response to interleukin-3 (IL-3), although the response was reduced as compared with control littermates. Compared with control cells, PU.1 null cells had minimal expression of G- and GM-CSF receptors and no detectable M-CSF receptors. The size of individual myeloid colonies produced from PU.1 null primitive and committed myeloid progenitors in the presence of IL-3, IL-6, and stem cell factor (SCF) were reduced compared with controls. Under these conditions, PU.1 null progenitors produced neutrophils but not monocytes/macrophages. These observations suggest that PU.1 gene disruption induces additional cell-autonomous effects that are independent of the alterations in myeloid growth factor receptor expression. Our results demonstrate that PU.1 gene disruption affects a number of developmentally regulated hematopoietic processes that can, at least in part, explain the changes in myeloid development and reduction in myeloid and neutrophil expansion observed in PU.1 null mice.
authors.affiliation: The Burnham Institute, La Jolla, CA, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Anderson
authors.forename: K A
authors.initials: KA
authors.lastname: Smith
authors.forename: K
authors.initials: K
authors.lastname: Conners
authors.forename: S R
authors.initials: SR
authors.lastname: McKercher
authors.forename: R A
authors.initials: RA
authors.lastname: Maki
authors.forename: B E
authors.initials: BE
authors.lastname: Torbett
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004351:Drug Resistance; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000473:pathology*; D007970:Leukopenia / Q000235:genetics / Q000473:pathology; D016131:Lymphocyte Subsets / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000172:deficiency; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000172:deficiency; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016173:Macrophage Colony-Stimulating Factor; D011518:Proto-Oncogene Proteins; D016186:Receptor, Macrophage Colony-Stimulating Factor; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1