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

Despite recent important advances in our understanding of the molecula r and biological abnormalities in chronic myelogenous leukemia (CML) t his new knowledge has not yet led to significant improvements in treat ment. We have reviewed what is known and still unknown about some of t he important properties of normal and leukemic stem cells and later pr ogenitor cells that may be relevant to developing improved treatment s trategies in the future. Clinical observations and experimental eviden ce strongly suggest that the major expansion of the CML population tak es place in the intermediate and later maturation compartments rather than in the stem cell or early progenitor cell compartments. The expan sion occurs slowly, probably taking several years to reach a trillion or more cells, at which time clinical symptoms begin to develop. The m aturing leukemic progenitors do not have an increased proliferative ra te, but they undergo one or more additional divisions and also live lo nger than comparable normal progenitors. Although no quantitative assa y system is available to study the ultimate proliferative potential of human stem cells, indirect evidence suggests that the behavior of leu kemic stem cells is not greatly different from that of normal stem cel ls. One important difference is that the leukemic stem cells (or early progenitor cells) do not curtail cell production until marrow cell de nsities are reached that are substantially higher than those at which normal stem cells cease production. Based on these and other considera tions a possible future therapeutic strategy is suggested. Any success ful treatment program for CML will probably depend on the inclusion of some type of specific drug(s) that will selectively affect leukemic p rogenitors. There is thus an urgent need to develop one or more select ive drugs for CML, perhaps somewhat analogous to the use of retinoic a cid for remission induction in acute promyelocytic leukemia.