Analysis of concentration-dependent functions of PU.1 in hematopoiesis using mouse models

Abstract

The Ets family transcription factor PU.1, encoded by the gene Sfpi1, is essential for normal hematopoiesis. A number of studies have suggested that changes in PU.1 concentration play a role in directing cell fate decisions during hematopoiesis. However, the stages of hematopoietic development at which changes in PU.1 concentration are important have not been defined until recently. Experiments using conditional null alleles, reporter alleles, and hypomorphic alleles of the Sfpi1 gene in mice demonstrate that PU.1 concentration is uniformly high during early stages of hematopoietic development. However, reduction of PU.1 concentration is required for normal development of megakaryocyte-erythroid progenitors, B cell progenitors, and T cell progenitors. PU.1 concentration increases in granulocyte-macrophage progenitors. Furthermore, experimental reduction of PU.1 concentration in the myeloid lineages leads to failed differentiation, abnormal proliferation, and leukemia. In this review, we summarize recent studies to develop a new model of PU.1 function in hematopoiesis.

Fig. 1

Lymphocyte development in mice homozygous for a hypomorphic allele of Sfpi1. A) Engraftment of wild type (WT) or Sfpi1^BN/BN fetal liver progenitors into RAG2^−/−il2rγ^−/− immunodeficient mice. The percentage of B220⁺ CD19⁺ B cells in the spleen of recipient mice (n = 5) was measured by flow cytometry six weeks after i.v. injection of 2 × 10⁶ fetal liver cells. B) Total cellularity of the thymus of wild type (WT) or Sfpi1^BN/BN mice. C) Flow cytometric analysis of single-cell suspensions from thymus of either wild type (WT) or Sfpi1^BN/BN mice at 10 days of age. Cells were gated for proper size and granularity and incubated with an antibody to the indicated cell surface markers. Numbers represent percentages of gated cells in each quadrant.

Fig. 2

A revised model for concentration-dependent function of PU.1 in hematopoiesis. The model of hematopoiesis shown is based on a revised model of hematopoiesis proposed by Adolfsson et al. [31]. PU.1 concentration is indicated by a gradient from red (high) to blue (low) in the top to bottom direction. The position of each cell type within this gradient indicates the relative concentration of PU.1. Mature megakaryocytes, erythrocytes, and T cells do not express PU.1. Abbreviations are as follows: HSC, hematopoietic stem cell; MPP, multipotential progenitor; LMPP, lymphoid-primed multipotential progenitor; CLP, common lymphoid progenitor; pro-B, progenitor B cell; B, mature B cell; pro-NK, progenitor natural killer cell; NK, mature natural killer cell; pro-T, progenitor T cell; T, mature T cell; MEP, megakaryocyte-erythroid progenitor; Meg, megakaryocyte; E, erythrocyte; GMP, granulocyte-macrophage progenitor; Mac, macrophage; Neut, neutrophil.