Alterations in genes that function in normal growth and development have been linked to malignant cell transformation. The mononuclear phagocyte colony-stimulating factor (CSF-1 or M-CSF) is a polypeptide growth factor synthesized by mesenchymal cells, which stimulates the survival, proliferation, and differentiation of haematopoietic cells of the monocyte-macrophage series. Multiple forms of soluble CSF-1 are produced by proteolytic cleavage of membrane-bound precursors, some of which are stably expressed at the cell surface. The c-fms proto-oncogene encodes the CSF-1 receptor, which is composed of an extracellular ligand-binding domain linked by a single membrane-spanning segment to a cytoplasmic tyrosine-specific protein kinase domain. Whereas the tyrosine kinase activity of the normal receptor is stimulated by CSF-1, mutations in the c-fms gene can constitutively activate the kinase to provide growth-stimulatory signals in the absence of the ligand. Oncogenic activation of the c-fms gene product appears to involve removal of a negative regulatory tyrosine residue near the carboxyl terminus of the receptor and one or more additional mutations that may simulate a conformational change induced by CSF-1 binding. Expression of the human c-fms gene in mouse NIH-3T3 cells confers a CSF-1 stimulated growth phenotype, indicating that receptor transduction is sufficient for fibroblasts to respond to a haematopoietic growth factor. In contrast, the v-fms oncogene induces factor-independent growth and tumorigenicity in factor-dependent myeloid cell lines, and contributes to the development of proliferative disorders of multiple haematopoietic lineages when introduced into murine bone marrow progenitors. Aberrant expression of an endogenous c-fms gene secondary to pro viral insertion and transcriptional activation has also been implicated in virus-induced myeloblastic leukaemia in mice. The c-fms and CSF-1 genes have been mapped on the long arm of human chromosome 5, a region that frequently undergoes interstitial deletions in certain haematopoietic disorders including acute myelogenous leukaemia. The study of CSF-1 and its receptor should provide information concerning the role of tyrosine kinases in regulating the normal growth and differentiation of haematopoietic cells and in contributing to their malignant transformation.

This content is only available via PDF.