CYTOKINETIC CONSIDERATIONS RELEVANT TO DEVELOPMENT OF A SUCCESSFUL THERAPEUTIC STRATEGY IN CHRONIC MYELOGENOUS LEUKEMIA (CML)

Despite recent important advances in our understanding of the molecular and biological abnormalities in chronic myelogenous leukemia (CML) this new knowledge has not yet led to significant improvements in treatment. We have reviewed what is known and still unknown about some of the important properties of normal and leukemic stem cells and later progenitor cells that may be relevant to developing improved treatment strategies in the future. Clinical observations and experimental evidence strongly suggest that the major expansion of the CML population takes place in the intermediate and later maturation compartments rather than in the stem cell or early progenitor cell compartments. The expansion occurs slowly, probably taking several years to reach a trillion or more cells, at which time clinical symptoms begin to develop. The maturing leukemic progenitors do not have an increased proliferative rate, but they undergo one or more additional divisions and also live longer than comparable normal progenitors. Although no quantitative assay system is available to study the ultimate proliferative potential of human stem cells, indirect evidence suggests that the behavior of leukemic stem cells is not greatly different from that of normal stem cells. One important difference is that the leukemic stem cells (or early progenitor cells) do not curtail cell production until marrow cell densities are reached that are substantially higher than those at which normal stem cells cease production. Based on these and other considerations a possible future therapeutic strategy is suggested. Any successful treatment program for CML will probably depend on the inclusion of some type of specific drug(s) that will selectively affect leukemic progenitors. There is thus an urgent need to develop one or more selective drugs for CML, perhaps somewhat analogous to the use of retinoic acid for remission induction in acute promyelocytic leukemia.