Role of PU.1 in Hematopoiesis

Abstract

The ETS-family transcription factor PU.1 is expressed in hematopoietic tissues, with significant levels of expression in the monocytic and B lymphocytic lineages. PU.1 is identical to the Spi-1 proto-oncogene which is associated with the generation of spleen focusforming virus-induced erythroleukemias. An extensive body of in vitro gene regulatory studies has implicated PU.1 as an important, versatile regulator of B lymphoid-and myeloid-specific genes. The first half of the review is designed to coalesce data generated from studies examining the two PU.1 "knockout" animals, which have prompted a reevaluation of the proposed function of PU.1 during hematopoiesis. During hematopoiesis, PU.1 is required for development along the lymphoid and myeloid lineages but needs to be downregulated during erythropoiesis. These unique functional characteristics of PU.1 will be exemplified by contrasting the function of PU.1 with other transcription factors required during fetal hematopoiesis. The second half of this review will reexamine the functional characteristics of PU.1 deduced from traditional biochemical and transactivation assays in light of recent experiments examining the functional behavior of PU.1 in an embryonic stem cell in vitro differentiation system. Working models of how PU.1 regulates promoter and enhancer regions in the B cell and myeloid lineage will be presented and discussed.

Signal transduction and the Ets family of transcription factors

“…One example of an Ets family member that is an important upstream regulator of cellular signaling is PU.1 (Fisher and Scott, 1998). Expression of PU.1 is restricted to cells of the hematopoietic lineage, including B cells and macrophages, and regulates the expression of growth factor and cytokine receptors.…”

Suppression of IL-12 Transcription in Macrophages Following Fcγ Receptor Ligation

“…PU.1 belongs to the Ets family of DNA binding proteins (25,26). It is expressed predominantly in macrophages, B cells, and erythroid cells (27,28).…”

Mouse models in the study of the Ets family of transcription factors

“…Initial reports suggested no detectable T Only detected in in vitro culture (Spain et al, 1999), homing defect (Fisher et al, 1999) Erythrocyte b Late embryonic anemia of variable severity Myeloid dendritic cells No commitment (Guerriero et al, 2000) Null (Iwama Post-natal An independently targeted Ets2 ES cell line exists, but the generation of knockout mice from these cells has not been reported, and the status of the targeted allele has not been determined ; b Not observed in C57BL/6 back-crossed mice (Fisher and Scott, 1998;Simon, 1998) cells in PU.1 mutant mice homozygous for the ®rst targeted allele (as evidenced by little or no Thy-1, CD4, or CD8 positive cells) (Scott et al, 1994). Subsequent fetal thymic organ culture indicated the presence of a small population of mature T cells, although the predominant population of thymocytes express cell surface markers corresponding to uncommitted T cell progenitors (Spain et al, 1999).…”

“…PU.1 7/7 ES cells were able to contribute to fetal but not adult erythropoiesis in chimeric mice, but PU.1 7/7 fetal hematopoietic progenitors were able to contribute to adult erythropoiesis in lethally irradiated adult recipients (Scott et al, 1997). The interpretation of this erythroid defect is further complicated by the loss of phenotype observed following back-cross onto a C57BL/6 background (Fisher and Scott, 1998;Simon, 1998).…”