The colony-stimulating factors and myeloid leukaemia.

The production of granulocytes and macrophages is under the control of at least four well defined haemopoietic growth factors or colony-stimulating factors (CSF's) which differ in their actions within the hierarchical organization of haemopoietic progenitor cells and in the different cell lineages they affect. Multi-CSF has an extremely broad haemopoietic specificity, GM-CSF stimulates all granulocyte and macrophage progenitor cells and G-CSF and M-CSF have actions essentially restricted to the granulocyte or macrophage cell lineages, respectively. They are each, however, required for cell survival, proliferation, differentiation and mature cell activation within the cell lineages they act on. They each exert their actions through specific high-affinity cell surface receptors which show no direct cross reactivity with each other and which are structurally distinct. However, at physiological temperatures the CSF's show a specific pattern of receptor co-down-modulation which might reflect their cell lineage specificities. A major defect in myeloid leukaemias is a block to differentiation so that cell divisions result in self-renewal of the leukaemic stem cells rather than terminal differentiation to non-dividing cells. In murine models such a defect does not result in malignancy until it is accompanied by autonomy from external CSF growth control but in human myeloid leukaemias there is no evidence for autonomy from CSF growth control and CSF's may play a permissive role in the emergence of myeloid leukaemias. The possibility of using CSF's to override the differentiation block in leukaemias and cause suppression of leukaemic growth by differentiation induction has been examined for the action of G-CSF on murine leukaemic WEHI-3B D+ cells. G-CSF induces differentiation in these cells, strongly suppresses cell divisions leading to self-renewal and increases the survival time of mice injected with treated cells. The possible importance of this factor in cell differentiation is indicated by the loss of G-CSF receptors in a differentiation-defective mutant of WEHI-3B, the conservation of G-CSF and its receptor from mouse to man and the observation that all primary human myeloid leukaemias exhibit specific receptors for this factor.