Hindawi Publishing Corporation International Journal of Cell Biology Volume 2011, Article ID 808524, 6 pages doi:10.1155/2011/808524 Review Article PU.1 and Haematopoietic Cell Fate: Dosage Matters Ka Sin Mak, Alister P. W. Funnell, Richard C. M. Pearson, and Merlin Crossley School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia Correspondence should be addressed to Merlin Crossley, m.crossley@unsw.edu.au Received 6 April 2011; Accepted 22 June 2011 Academic Editor: Andre Van Wijnen Copyright © 2011 Ka Sin Mak et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The ETS family transcription factor PU.1 is a key regulator of haematopoietic diﬀerentiation. Its expression is dynamically controlled throughout haematopoiesis in order to direct appropriate lineage speciﬁcation. Elucidating the biological role of PU.1 has proved challenging. This paper will discuss how a range of experiments in cell lines and mutant and transgenic mouse models have enhanced our knowledge of the mechanisms by which PU.1 drives lineage-speciﬁc diﬀerentiation during haematopoiesis. 1. Introduction Haematopoiesis is a lifelong process that generates the range of blood cell types that exhibit distinct and specialised functions. Transcription factors play a critical role in this complex and highly orchestrated process, directing multi- potent haematopoietic stem cells (HSCs) towards lineage commitment by regulating lineage-speciﬁc gene expression, proliferation, and diﬀerentiation. The ETS family member PU.1 is one such transcription factor. The PU.1 gene was ﬁrst identiﬁed as a proviral inte- gration site for the spleen focus forming virus (SFFV) in erythroleukaemias [1]. SFFV integration in the PU.1 locus leads to increased PU.1 transcription and subsequent erythroleukaemic transformation. It has since emerged that PU.1 is one of the major haematopoietic regulators, with a particular role in directing diﬀerentiation within the myeloid and lymphoid pathways [2]. Several PU.1 and mutant mouse lines have been generated and exhibit varied phenotypes depending on the nature of PU.1 defect [3]. PU.1 knockout mice succumb to neonatal death and show a marked lack of myeloid cells, T and B cells [4, 5]. Erythro- poiesis is also altered in the foetal livers of PU.1 mice with erythroid progenitors displaying reduced self-renewal capacity and a propensity to diﬀerentiate prematurely [6]. PU.1 is thus crucial in directing many facets of haematopoiesis and concordant with this, its expression ﬂuctuates dynamically in the various haematopoietic diﬀer- entiation pathways (Figure 1). Importantly, the regulation of diﬀerentiation by PU.1 is not merely via a “presence or absence of expression” mechanism but by a dose-dependent eﬀect. For instance, the expression of PU.1 is low in long- term reconstituting (LT)-HSCs but rises as these progenitors become more lineage restricted and form precursor cells known as common myeloid progenitors (CMPs) and com- mon lymphoid progenitors (CLPs). Upon further lineage diﬀerentiation and maturation, PU.1 is expressed at varied levels in mature blood cells, with higher levels found in macrophages than B cells and low levels in mature erythroid cells, megakaryocytes, and T cells [7–9]. Moreover, not only is PU.1 diﬀerentially expressed in the various haematopoietic cells, but also lineage speciﬁcation is sensitive to, and directed by, the varied dosage of PU.1 in diﬀerentiating progenitor cells. In addition, inappropriate expression of PU.1 in speciﬁc haematopoietic cells can result in leukaemic transformation, as in the case of T-cell lymphomas and, as mentioned previously, erythroleukaemias [10, 11]. This paper focuses on how the expression pattern of PU.1 diﬀers between diﬀerent committed precursors and how this serves to determine cell fate. The interplay between PU.1 and other antagonistic haematopoietic regulators will also be discussed. 2. PU.1 Levels Are Important in Directing Haematopoietic Progenitor Cell Fate PU.1 expression in HSCs is important for their self-renewal and for their development into CMPs and CLPs [12]. These