title: Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation.
abstract: The PU.1 transcription factor is a key regulator of hematopoietic development, but its role at each hematopoietic stage remains unclear. In particular, the expression of PU.1 in hematopoietic stem cells (HSCs) could simply represent "priming" of genes related to downstream myelolymphoid lineages. By using a conditional PU.1 knock-out model, we here show that HSCs express PU.1, and its constitutive expression is necessary for maintenance of the HSC pool in the bone marrow. Bone marrow HSCs disrupted with PU.1 in situ could not maintain hematopoiesis and were outcompeted by normal HSCs. PU.1-deficient HSCs also failed to generate the earliest myeloid and lymphoid progenitors. PU.1 disruption in granulocyte/monocyte-committed progenitors blocked their maturation but not proliferation, resulting in myeloblast colony formation. PU.1 disruption in common lymphoid progenitors, however, did not prevent their B-cell maturation. In vivo disruption of PU.1 in mature B cells by the CD19-Cre locus did not affect B-cell maturation, and PU.1-deficient mature B cells displayed normal proliferation in response to mitogenic signals including the cross-linking of surface immunoglobulin M (IgM). Thus, PU.1 plays indispensable and distinct roles in hematopoietic development through supporting HSC self-renewal as well as commitment and maturation of myeloid and lymphoid lineages.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Chamorro
authors.initials: C
authors.lastname: Somoza
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Shigematsu
authors.forename: Estelle A
authors.initials: EA
authors.lastname: Duprez
authors.forename: Junko
authors.initials: J
authors.lastname: Iwasaki-Arai
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Mizuno
authors.forename: Yojiro
authors.initials: Y
authors.lastname: Arinobu
authors.forename: Kristin
authors.initials: K
authors.lastname: Geary
authors.forename: Pu
authors.initials: P
authors.lastname: Zhang
authors.forename: Tajhal
authors.initials: T
authors.lastname: Dayaram
authors.forename: Maris L
authors.initials: ML
authors.lastname: Fenyus
authors.forename: Shannon
authors.initials: S
authors.lastname: Elf
authors.forename: Susan
authors.initials: S
authors.lastname: Chan
authors.forename: Philippe
authors.initials: P
authors.lastname: Kastner
authors.forename: Claudia S
authors.initials: CS
authors.lastname: Huettner
authors.forename: Richard
authors.initials: R
authors.lastname: Murray
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D006410:Hematopoiesis / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology; D008099:Liver / Q000196:embryology / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1