Combinatorial control of gene expression in the hematopoietic system
The common view is that hematopoiesis navigates along mostly irreversible, hierarchical cell differentiation routes, with hematopoietic stem cells (HSC) on the topmost level, lineage committed precursor cells towards the intermediate level and terminally differentiating cells at the lowest level (Figure 1). The hierarchy between progenitor proliferation and terminal differentiation is reflected in the distribution of stage and lineage-specific transcription factors. Ablation and over expression of transcription factors have suggested that multipotent progenitors depend on early transcription factors, such as the basic helix-loop-helix protein SCL, the runt domain protein AML1, and the c-Myb protein, whereas differentiation into one of the eight lineages depends on additional transcription factors such as zinc finger proteins (e.g. Ikaros, EKLF, GATA1 and FOG1; lymphoid, erythroid and eosinophil lineage), ets-domain proteins (e.g. PU.1; myeloid and B-lymphoid lineage), bZip proteins (e.g. C/EBPα,β or MafB; neutrophil, eosinophil, and macrophage lineage), or the paired box protein Pax 5 (B-cell).