Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation

Hiromi Iwasaki, Chamorro Somoza, Hirokazu Shigematsu, Estelle A. Duprez, Junko Iwasaki-Arai, Shin Ichi Mizuno, Yojiro Arinobu, Kristin Geary, Pu Zhang, Tajhal Dayaram, Maris L. Fenyus, Shannon Elf, Susan Chan, Philippe Kastner, Claudia S. Huettner, Richard Murray, Daniel G. Tenen, Koichi Akashi

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259 Citations (Scopus)

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 myelolymphold 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 m situ could not maintain hematopoiesis and were outcompeted by normal HSCs. PU.1-deficient HSCs also failed to generate the earliest myeloid and lymphold 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 immunoglobulln 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.

Original languageEnglish
Pages (from-to)1590-1600
Number of pages11
JournalBlood
Volume106
Issue number5
DOIs
Publication statusPublished - Sep 1 2005
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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