Available online at www.sciencedirect.com Transcription control of early B cell differentiation Elizabeth M Mandel and Rudolf Grosschedl Differentiation of B lymphocytes involves the step-wise acquisition of a specialized phenotype that depends on the expression of lineage-specific genes and the repression of genes characteristic of multipotent progenitors and alternate lineages. The early steps of B lineage specification and commitment are, partly, controlled by the well- characterized transcription factors Ikaros, Pu.1, E2A, early B cell factor-1, and Pax5 that act in a complex regulatory network. However, our understanding of B cell differentiation is far from complete. Recent work has shed light on the mechanisms by which transcription factors implement cell type-specific gene expression patterns and epigenetic changes in chromatin that allow for B lineage specification and commitment. Address Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology, Stu ¨ beweg 51, 79108 Freiburg, Germany Corresponding author: Grosschedl, Rudolf (grosschedl@immunbio.mpg.de) Current Opinion in Immunology 2010, 22:161–167 This review comes from a themed issue on Lymphocyte Development Edited by Ellen Rothenberg and Cornelis Murre Available online 9th February 2010 0952-7915/$ – see front matter # 2010 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2010.01.010 Introduction The generation of antibody-producing B lymphocytes represents a paradigm for a terminal differentiation pro- cess in which regulatory networks of signaling cascades, transcription factors and epigenetic modifiers allow for the step-wise conversion of a multipotent stem cell into a highly specialized cell type [1]. Differentiated B cells are derived from progenitor cell populations with increas- ingly limited developmental potential, which themselves originate from hematopoietic stem cells in the fetal liver and adult bone marrow [2,3]. Recent work to more fully decipher the events leading to the differentiation of mature B cells has not only furthered our understanding of the cell fate potential and lineage commitment of differentiating B cells, but also shed light on the mol- ecular mechanisms underlying this developmental pro- gression. In this review, we address our current understanding of the steps leading up to the lineage commitment of B cells and the transcription factors that most strongly influence this series of events, both from a transcriptional and an epigenetic perspective. Lineage specification and commitment: from stem cells to B cells All mature cell types of the blood originate from a pluripotent population of hematopoietic stem cells (HSCs) that reside in the fetal liver before birth or bone marrow after birth. A gain of specific gene expression signatures (specification) and the gradual loss of differ- entiation potential for alternative cell lineages (commit- ment) eventually lead to the generation of a specific B cell population. Classical models for hematopoietic cell differ- entiation have proposed a mechanism by which two lin- eage-restricted populations, termed common lymphoid progenitors (CLPs) and common myeloid progenitors (CMPs), are derived from a common pool of multipotent progenitors (MPPs) lacking the self-renewal capacity of their HSC precursors [4–6]. Several lines of evidence have proposed that CLPs are the common branch point for the generation of the NK cell, T cell, and B cell lineages, while granulocytes, megakaryocytes, and eryth- rocytes of the myeloid lineage are generated from CMPs [4,5]. However, recent work has challenged this view by implicating a progressive, asymmetric loss of lineage potential governed by the concerted upregulation and downregulation of distinct lineage programs rather than a precise, step-wise process of commitment [2,3,7]. During the initial phases of lymphocyte development, multipotent, self-renewing HSCs differentiate into multi- potent progenitors, characterized by the loss of self- renewal capacity and the acquisition of Flt3 tyrosine kinase expression (Figure 1)[8]. Although increasing expression of Flt3 has been associated with the progressive loss of myeloid potential, the MPP population retains multi-lin- eage differentiation potential [6,8,9]. Refined characteriz- ations of the MPP population by either Pu.1 and Gata1 expression, or that of Flt3 and vascular cell adhesion molecule (VCAM)-1, suggest the existence of at least three distinct subsets that differ in their ability to give rise to the megakaryocyte, granulocyte/macrophage, and erythroid lineages [10,11]. MPPs also generate lymphoid-primed multipotent progenitors (LMPPs) and subsequently, the common lymphoid progenitor compartment (Figure 1) [8,10–13]. Contrary to previous work, recent studies suggest that T cell commitment may first occur at a stage before the CLP stage, whereas others have demonstrated that even cells at the pro-B cell stage retain limited B/T lymphocyte plasticity [14,15]. Additionally, the CLP com- partment has been described as a heterogeneous popu- lation that even contains a small number of B lineage cells www.sciencedirect.com Current Opinion in Immunology 2010, 22:161–167