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The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia

CORRESPONDENCE Stephen L. Nutt: nutt{at}wehi.edu.au

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.

Abbreviations used: AML, acute myeloid leukemia; C/EBP, CCAAT/enhancer binding protein ; CLP, common lymphoid progenitor; CMP, common myeloid progenitor; EPO, erythropoietin; ES, embryonic stem; G-CSF, granulocyte colony-stimulating factor; GMP, granulocyte-macrophage progenitor; HSC, hematopoietic stem cell; IRES, internal ribosome entry site; IRF, interferon regulatory factor; lin^–, lineage-negative; LF, lactoferrin; LIF, leukemia inhibitory factor; M-CSF, macrophage-CSF; MEP, megakaryocyte-erythrocyte progenitor; polyIC, polyinosine-polycytosine; SCF, stem cell factor.

L. Wu and S.L. Nutt contributed equally to this work.

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