Seminars in Immunology 20 (2008) 205–206

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Seminars in Immunology

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Editorial

Lymphoid myeloid lineage specification

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The hematopoietic system has long been a paradigm to studyow adult type stem cells diversify into different lineages. Onceematopoietic stem cells (HSCs) lose their ability to self renewhey become progressively restricted in their differentiation poten-ial. Diversification is a hierarchical process that can be visualizedn lineage trees. This process is driven by transcription factorsnd microRNAs, whose activities can respond to signaling fromhe microenvironment. Once changes in gene expression arenduced they are stabilized by chromatin modifications. Com-

itment is typically preceded by the low level expression inultipotent progenitors of lineage-restricted genes. During differ-

ntiation expression of these genes is successively either reinforcedr repressed, leading to the formation of specialized cells thatxhibit markers and functions characteristic for a particular lineage.

There has been much controversy about how myeloid and lym-hoid lineages, the constituents of the innate and adaptive immuneystem respectively, branch from each other. Although the progresschieved in this area over the past few years have helped clarify-ng some of the issues, things have become also more complicated.he first two reviews start by discussing the latest models of earlyineage specification. The following four reviews mechanisms driv-ng the formation B cells, T cells and myeloid cells, focusing on theole of transcription factors and micro RNAs. The issue ends withreview on the chromatin changes induced during transcription

actor induced commitment of myeloid cells.The articles of Luc et al. and Lai and Kondo address the issue

f how the earliest hematopoietic progenitors, cells within the so-alled LSK compartment (Lin-/low, Sca-1+, Kit+) become restrictedn their developmental potential. It is now clear that the first steps the formation of a subset of LSK cells that loses the ability toorm erythrocytes and megakaryocytes, but retains the potentialo generate all cells of the immune system. However, what initiallyppeared to be a series of simple binary decisions turned out to beore a gradual change in differentiation probabilities, complicat-

ng attempts to draw a well defined and uncontested early lineageree. In addition, although much has been learned from defining theells’ differentiation potential in vitro or after transplantation thesessays only partially reconstruct the cells differentiation potentialn vivo. As Luc et al. put it: future efforts are needed for the ‘devel-pment of reliable reporter systems allowing dynamic tracking ofhe commitment process’

The regulatory network that defines the B cell lineage is one of

he best understood to date. The reviews of Lukin et al. and Laslo etl. describe the fundamental role of the transcription factor EBF1.his factor becomes upregulated at the common lymphoid progen-tor stage and is embedded in a regulatory network that involves

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2A and Pax5. The network, which is stabilized by feedback loops,nsures total repression of lineage inappropriate gene expression,uch as myeloid or T cell genes. Laslo et al. also extensively discusseshe role of PU.1 and C/EBP� as primary lineage determinants thatpecify macrophage and granulocyte development. They reviewata from their own lab showing that a second layer of transcrip-ion factors (‘secondary lineage determinants’) refine the decisionsithin the myeloid compartment, leading to the alternative forma-

ion of macrophages or granulocytes. Finally, they discuss the rolef two microRNA systems that modulate the expression of myeloidssociated transcription factors, leading to a reinforcement of theormation of either macrophages or granulocytes.

Rothenberg and Scripture-Adams discuss T cell fate choice, sin-ling out GATA-3, PU.1 and Notch as key determinants. Here, Notchlays a unique role as a receptor that becomes a transcription

actor following signaling induced by ligand that is expressed byhymic stromal cells. Notch signaling inhibits alternative choicesn a sequential manner, with B cell developmental potential beingost before myeloid/dendritic and NK cell potentials. However, ashey point out, ‘Notch is not a Boolean operator that determines Tineage fate at a stroke, but a quantitatively modulated participantn protracted lineage decisions’. Like at the branching between Bnd myeloid lineage cells, myeloid fate decisions are effected byhe expression PU.1 and C/EBP�, and are counteracted by Notchnd GATA-3. T cell commitment thus provides a particularly clearxample of how cell fate decisions are influenced by the cells’icroenvironment, directly feeding into antagonistic regulatory

etworks.The article by Greig et al. discusses the role of Myb, a tran-

cription factor originally identified as an oncogene in acute avianeukemia. Myb, which initially was thought to be required for theormation of definitive HSCs in the fetal liver, is now thought toe mainly needed for their expansion and perhaps differentiation.his factor is surprisingly versatile in its recurrent use in differ-nt lineages and at different stages of development. Besides itsole for red blood cell precursor proliferation and megakaryocyteunction it is required for the progression of early T and B cell devel-pment. The latter role is attenuated by mir150, a microRNA thatnhibits Myb expression. However, there is still surprisingly littlenown about how Myb interacts with the various lineage specificegulatory networks, knowledge that is essential to understand itsersatility.

The last review, by Bonifer et al., discusses the interplay betweenhe myeloid associated transcription factor PU.1 and chromatinomponents in the specification of myeloid cells. Here, studiesn the macrophage restricted CSF-1 (M-CSF) receptor gene have

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06 Editorial / Seminars in Im

hown that commitment to the myeloid lineage is a two-step pro-ess that is initiated by binding of PU.1 to the CSF-1R promoter andater extended to the enhancer of the gene. This leads to the subse-uent chromatin remodeling of the respective regulatory elements

nd epigenetic stabilization of the changes induced.

The topics discussed in this issue are important not only for thenderstanding of fundamental processes of lineage specification,ut are also relevant for understanding leukemogeneiss, as manyf the transcription factors discussed can act as oncogenes, or in

logy 20 (2008) 205–206

ome cases, as tumor suppressors. Moreover, as succinctly sum-arized by Laslo et al. ‘progress in this area will also facilitate the

irected and efficient generation of specific immune cells and theiranipulation for cell based therapies’.

Thomas GrafCancer and Differentiation, CRG,

Barcelona, SpainE-mail address: thomas.graf@crg.es