Reduction in PU.1 activity results in a block to B-cell development, abnormal myeloid proliferation, and neonatal lethality

Exp Hematol. 2007 Jul;35(7):1056-68. doi: 10.1016/j.exphem.2007.04.005.


Objective: It has been demonstrated that high concentration of the transcription factor PU.1 (encoded by Sfpi1) promotes macrophage development, whereas low concentration induces B-cell development in vitro. This has led to the hypothesis that lower levels of PU.1 activity are required for B cell than for macrophage development in vivo. We utilized an allele of Sfpi1 (termed BN) with a mutation in the first coding exon, which resulted in a reduction of PU.1 expression in order to test this hypothesis.

Materials and methods: Using gene targeting in embryonic stem cells, two ATG-start site codons of PU.1 were mutated, resulting in reduced PU.1 expression originating from a third start codon. Mice were assayed for phenotypic abnormalities using fluorescence-activated cell sorting, microscopy, and colony-forming ability. In addition, isolated cells were tested for their differentiation potential in vitro and in vivo.

Results: Lymphoid and myeloid cells derived from cultured Sfpi1(BN/BN) fetal liver cells had reduced levels of PU.1 expression and activity. B-cell development was intrinsically blocked in cells isolated from Sfpi1(BN/BN) mice. In addition, myeloid development was impaired in Sfpi1(BN/BN) fetal liver. However, neonatal Sfpi1(BN/BN) mice had a dramatic expansion and infiltration of immature myeloid cells.

Conclusion: Contrary to our original hypothesis, high levels of PU.1 activity are required to induce both myeloid and B-cell development. In addition, neonatal mice homozygous for the hypomorphic allele acquire a myeloproliferative disorder and die within 1 month of age.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Animals
  • Animals, Newborn
  • B-Lymphocytes / physiology*
  • Cell Proliferation
  • Cells, Cultured
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Myelopoiesis
  • Myeloproliferative Disorders / etiology*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Trans-Activators / genetics
  • Trans-Activators / physiology*


  • Proto-Oncogene Proteins
  • Trans-Activators
  • proto-oncogene protein Spi-1