Biological strategies for the selective manipulation of normal and leukemic stem cells

Recent developments have occurred in the identification and quantitation of a very primitive type of hematopoietic cell (referred to as a long-term culture initiating cell or LTC-IC) using defined long-term culture conditions. These have facilitated investigations of the numbers and properties of both normal and leukemic LTC-IC in patients with chronic myeloid leukemia (CML). Such studies have revealed that the marrow of many chronic phase patients contains a substantial population of normal LTC-IC that are functionally intact albeit suppressed in vivo. Leukemic LTC-IC are typically less numerous in the marrow of these patients but are found in elevated numbers in the peripheral blood which, on average, in total contains more leukemic LTC-IC than the marrow when the WBC count rises above 10(11) per liter. However, a very marked heterogeneity in all of these parameters exists among individual patients. Some of the properties of leukemic LTC-IC are indistinguishable from those of their normal counterparts. Others, particularly those typically associated with an activated state, are altered, although frequently in only 90% (or less) of the leukemic LTC-IC. A more marked disparity between primitive normal and leukemic LTC-IC is seen in terms of their relative abilities to maintain their numbers in vitro. At the level of primitive clonogenic cells, the leukemic population has been shown to exhibit an increased rate of turnover. This appears to be due to an inability of these cells to respond to the cytostatic effects of macrophage inflammatory protein-1 alpha (MIP-1 alpha). These findings provide new insights into the biology of CML and highlight the power of quantitative assays to guide the development of more generally applicable curative therapies.