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REVIEWS
Progress in the isolation, functional investigation and targeted manipulation of defined stem-cell and progenitor-cell stages has highlighted the role of the myeloid system as a model to understand basic mechanisms of cell differentiation. In parallel to the advances in the isolation of myeloid precursors are recent discoveries of the molecular events that determine myeloid development. Another advantage of the myeloid system as model for cell differentiation is that neoplasms originating from transformed myeloid cells, such as acute and chronic myeloid leukaemias (BOX 1), are among the most studied and best understood entities in human cancer.
Transcription factors with mainly cell-type-restricted expression patterns have been recognized as key components in the orchestration of myeloid-cell maturation1. Each of these nuclear proteins drives expression of a characteristic set of lineage-specific target genes, thereby instructing a precursor cell to adopt a certain differentiation programme. The interplay among these transcription factors and their expression levels in cells during crucial developmental stages are key parameters in the establishment of cell fates2. Furthermore, dysregulation of transcription factor activity has an important role in leukaemia, implicating these genes as potential targets for therapeutic intervention in myeloid and other cancers3.
In this article, we review the current picture of myeloidlineage development from haematopoietic stem cells (HSCs), and we focus on the important role of transcription factors in controlling this multistep process.
Ordered progenitor hierarchy from HSCs
Enormous progress has been made in recent years in defining the precursor hierarchy that underlies the development of cells of the haematopoietic system, and these advances now define our thinking about the development of myeloid cells. Using multicolour flow cytometry, the Weissman laboratory in particular succeeded in identifying an ordered sequence of pheno-typically distinct stem-cell and intermediate-precursor populations, allowing for the first time the prospective isolation and characterization of these populations
(FIG. 1a). The Weissman model proposes that long-term HSCs (defined phenotypically as LINIL-7R SCA1+KIT+FLT3Thy1lowCD34) are included within a low-frequency bone-marrow subpopulation with the unique ability for life-long self-renewal and multilineage differentiation potential48. Long-term HSCs give rise to short-term HSCs (LINIL-7RSCA1+KIT+FLT3low Thy1lowCD34+), which retain the ability for multi lineage differentiation potential, but have decreased self-renewal potential9,10. The next phenotypically distinct precursor population, the multipotential progenitors (MPPs; LINIL-7RSCA1+KIT+FLT3lowhiThy1CD34+), has lost self-renewal potential completely, but maintains the ability to...