STEM CELL KINETICS

Chronic myeloid leukaemia (CML) is a transplantable multi-lineage disease. In its initial chronic phase, the leukaemic clone exhibits a hierarchical structure that closely resembles normal haematopoiesis. Thus assays for in vitro colony-forming cells (CFC) and their more primitive precursors identified as long-term culture-initiating cells (LTC-IC) detect subsets of Ph + /BCR-ABL + cells which cannot be readily distinguished from their normal counterparts. The use of these assays to examine the numbers, properties, genotype, distribution and regulation of primitive progenitors in patients' blood and marrow samples have revealed a number of unique and unexpected findings. These suggest that the indolent nature of the chronic phase of the disease may be explained by competing effects of the BCR-ABL gene product on the commitment to differentiate, control of cell cycle progression and apoptosis. As a result, the amplification of BCR-ABL + stem cells is constrained but the expansion of their progeny is enhanced and, on the granulocyte pathway, this expansion proceeds unchecked to the stage of mature end cell production resulting in the leukaemic picture observed.