PU.1 regulates the commitment of adult hematopoietic progenitors and restricts granulopoiesis.
Although the transcription factor PU.1 is essential for fetal lymphomyelopoiesis, we unexpectedly found that elimination of the gene in adult mice allowed disturbed hematopoiesis, dominated by granulocyte production. Impaired production of lymphocytes was evident in PU.1-deficient bone marrow (BM), but myelocytes and clonogenic granulocytic progenitors that are responsive to granulocyte colony-stimulating factor or interleukin-3 increased dramatically. No identifiable common lymphoid or myeloid progenitor populations were discernable by flow cytometry; however, clonogenic assays suggested an overall increased frequency of blast colony-forming cells and BM chimeras revealed existence of long-term self-renewing PU.1-deficient cells that required PU.1 for lymphoid, but not granulocyte, generation. PU.1 deletion in granulocyte-macrophage progenitors, but not in common myeloid progenitors, resulted in excess granulocyte production; this suggested specific roles of PU.1 at different stages of myeloid development. These findings emphasize the distinct nature of adult hematopoiesis and reveal that PU.1 regulates the specification of the multipotent lymphoid and myeloid compartments and restrains, rather than promotes, granulopoiesis.
Dakic
Aleksandar
A
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
Metcalf
Donald
D
Di Rago
Ladina
L
Mifsud
Sandra
S
Wu
Li
L
Nutt
Stephen L
SL
D000818:Animals; D000911:Antibodies, Monoclonal; D001772:Blood Cell Count; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D017931:DNA Primers; D005434:Flow Cytometry; D005822:Genetic Vectors; D005838:Genotype; D006098:Granulocytes / Q000378:metabolism / Q000502:physiology*; D049452:Green Fluorescent Proteins; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
D000911:Antibodies, Monoclonal; D017931:DNA Primers; D049452:Green Fluorescent Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1