Normal myelopoiesis is essential to normal host defense. It involves the regulated production of new myeloid cells, including neutrophilic, eosinophilic, and basophilic granulocytes, as well as monocytes and macrophages. The process is driven by several growth factors that control both the rate of cell production and their subsequent function. Thus, an understanding of normal myelopoiesis requires knowledge of individual cell characteristics and the expected responses of these cells to disease states.
The myeloid cells share a common progenitor known as the colony-forming unit–granulocyte, monocyte (CFU-GM). This cell arises from earlier progenitors, which are capable of giving rise to myeloid, megakaryocytic, and lymphoid lineages, and ultimately from the multipotent stem cell, which is capable of differentiation into all hematopoietic cell lines (Figure 16-1). The progeny of the CFU-GM are capable of differentiating toward granulocytes or monocytes and macrophages. There is a well-recognized pattern of morphology that can be used to evaluate the later stages of differentiation of the myeloid cell lines (Figure 16-2).
Stem cell differentiation and growth factors. The central differentiation pathway from totipotent stem cell to committed progenitors is regulated by numerous interleukins and growth factors. With the exception of erythropoietin, none of these factors is entirely specific for a single lineage. They interact with each other and have broad effects at several stages of the differentiation pathways.
The sequence of neutrophil differentiation—morphology. Neutrophils have several stages of differentiation that are easily distinguished by morphology. Changes in staining properties of the granules, the shape of the nucleus, and the chromatin pattern can be used to distinguish each stage, although intermediate stages are commonly seen in normal and abnormal marrow.
The several myeloid growth factors that are known to influence the differentiation of the CFU-GM are shown in Figure 16-1. These growth factors interact with membrane receptors of the cytokine receptor superfamily, including interleukin (IL)-3, IL-5, and granulocyte macrophage colony-stimulating factor (GM-CSF). These receptors share a common β chain, which explains the overlap of responses resulting from stimulation by these cytokines. They lack specific tyrosine kinase activity. Upon ligand binding, the common β chain and specific α chain dimerize and are able to trigger progenitor cell transcription factor proteins Jak-STAT, RAS, NF-κB, and PI3-kinase, which control the expression of the genes involved in cell differentiation. Thus, in order for a progenitor cell to proceed down a unique pathway of differentiation, it must express 1 or more transcription factors that, when activated by a growth factor receptor, in turn activate the family of genes required for that pathway.
The marrow microenvironment (stromal cells) also ...