STEM-CELL RENEWAL AND DETERMINATION DURING CLONAL EXPANSION IN NORMAL AND LEUKEMIC HEMATOPOIESIS

Normal haemopoiesis is a cellular hierarchy headed by pluripotent stem cells capable of both self renewal and, after determination, the generation of differentiating lineages that end in terminal functional cells. The role of stem cells is crucial because only these have the capacity to generate clonal populations during development or after injury. During clonal expansion the cells are affected by many sets of receptors and ligands. These belong to at least two classes: one consists of growth factors that bind cell surface receptors and initiate signalling events; the other class contains receptors which act as ligand-dependent transcription factors such as the intracellular steroid superfamily. In spite of this elaborate regulatory apparatus, control during clonal expansion is lax, perhaps stochastic, as evident from the great heterogeneity disclosed by examining the cellular compositions of haemopoietic clones. It may be that the large number of signals impinging on binary possible outcomes (for example self-renewal or determination) serve to set probabilities rather than to determine outcomes. In leukaemia, many of the features of normal haemopoiesis are retained. The disease begins as transformations in normal stem cells; after additional leukaemogenic events clonal expansion yields malignant populations which are clonal in each affected individual. These dominant clonal populations retain the hierarchical organization found in the normal, the major difference is that post-deterministic divisions in leukaemia yield descendants that retain primitive (blast) morphology although proliferative capacity is lost. In acute myeloblastic leukaemia (AML) cell culture methods are available that permit the measurement of clonogenic blast stem cells. These methods have shown that regulatory mechanisms active in normal haemopoiesis are retained in AML, including lax regulation during clonal expansion. The biological features of blast stems cells displayed by the culture technique reflect in part, events in vivo, as associations have been found between results in cell culture and clinical outcome. Thus, study of leukaemic populations provides a challenge for basic science and an opportunity for successful application in control of disease.