In addition to these features of normal cells, the finding that a common subset of acute myeloid leukemia has both a granulocytic and monocytic cellular component further underscores the close developmental relationship of neutrophils and monocytes. Granulocyte-Colony Stimulating Factor (G-CSF) enables the formation of CFU-G in methylcellulose cultures, Macrophage-Colony Stimulating Factor (M-CSF, CSF-1) enables the growth of CFU-M, and Granulocyte/Macrophage-Colony Stimulating Factor (GM-CSF) or Interleukin-3 (IL-3) enable the proliferation of CFU-G, CFU-M, and CFU-GM.
These progenitors in turn give rise to granulocyte-, monocyte-, and granulocyte/monocyte-colony forming units (CFU-G, CFU-M, and CFU-GM). Pluripotent hematopoietic stem cells in fetal liver or in adult marrow give rise to granulocyte/macrophage progenitors (GMPs), characterized by expression of CD34 and Fcγ Receptor(II/III) ( Akashi et al., 2000 Traver et al., 2001). Polymorphonuclear and mononuclear phagocytes function in host defense against infections and are capable of recognizing, ingesting, and destroying foreign materials and organisms. CBF and c-Myb stimulate proliferation whereas C/EBPα induces a G1/S arrest cell cycle arrest is required for terminal myelopoiesis, perhaps due to expression of p53 or hypo-phosphorylated Rb. Higher levels of PU.1 are required for monopoiesis than for B-lymphopoiesis, and higher C/EBP levels may favor granulopoiesis over monopoiesis. PU.1 and C/EBPα activate their own promoters, C/EBPα rapidly induces PU.1 and C/EBPε RNA expression, and RARα activates the C/EBPε promoter. c-Jun:PU.1, ICSBP:PU.1, and perhaps Maf:Jun complexes induce monocytic genes. PU.1:GATA-1 interaction and C/EBP suppression of FOG transcription inhibits erythroid and megakaryocyte gene expression. Orchestration of the myeloid developmental program is achieved via cooperative gene regulation, via synergistic and inhibitory protein–protein interactions, via promoter auto-regulation and cross-regulation, via regulation of factor levels, and via induction of cell cycle arrest: For example, c-Myb and C/EBPα cooperate to activate the mim-1 and NE promoters, PU.1, C/EBPα, and CBF, regulate the NE, MPO, and M-CSF Receptor genes. Signals eminating from cytokine receptors modulate factor activities but do not determine cell fates.
Monopoiesis can be induced by Maf-B, c-Jun, or Egr-1 and is dependent upon PU.1, Sp1, and ICSBP. Early granulopoiesis requires the C/EBPα, PU.1, RAR, CBF, and c-Myb transcription factors, and terminal neutrophil differentiation is dependent upon C/EBPε, PU.1, Sp1, CDP, and HoxA10. Granulocytes and monocytes develop from a common myeloid progenitor.
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