Leukemic stem cells: where have they gone wrong?

What is the mechanism behind acute bilineage leukemia (ie, 2 separate populations of myeloid and lymphoid blasts)? Why does the risk for therapy-related myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) last only 10 years, while the risk for therapy-related solid tumors can be lifelong? Recent work from several groups is beginning to provide insights into these and other important questions in leukemia biology.

Substantial progress has been made in identifying and isolating normal hematopoietic stem cells. There is general agreement that normal hematopoietic stem cells are small-sized cells that do not express lineage-specific antigens (ie, are lin⁻ or CD38⁻) and are usually in the G₀ phase of the cell cycle. But other characteristics that define hematopoietic stem cells have been a matter of debate. For example, it now appears that there are CD34⁻, as well as CD34⁺, hematopoietic stem cells. One explanation for the reported differences regarding hematopoietic stem cells is that there are several classes of these cells with varying capacity for long-term production of the different hematologic lineages. Van Zant and colleagues (Exp Hematol. 1997;25:187–192) have used the term high-qualityfor hematopoietic stem cells that are capable of lifelong production of all hematologic lineages and low-quality for those hematopoietic stem cells that yield only limited hematologic reconstitution.

Chronic myeloid leukemia (CML) and MDS have long been considered stem cell disorders. The leukemic stem cells in these diseases appear to be CD34⁺ and lin⁻/CD38⁻. But although B cells are sometimes derived from the leukemic clone in these diseases, T cells are virtually never involved. Moreover, normal stem cells can be separated from leukemic stem cells in these diseases using characteristics (such as small size and low class II expression) of high-quality hematopoietic stem cells. Thus CML and MDS stem cells appear to have characteristics of low-quality,rather than high-quality, stem cells. Many groups have now shown that most cases of AML also arise from CD34⁺lin⁻/CD38⁻ stem cells. George and colleagues (page 3925) demonstrate that acute lymphoblastic leukemia stem cells also often exhibit a similar phenotype. Feuring-Buske and Hogge (page 3882) showed that another characteristic of high-quality hematopoietic stem cells, rapid efflux of the fluorescent vital DNA binding dye Hoechst 33342, can be used to separate normal from leukemic stem cells.

Like CML and MDS, many if not most cases of acute leukemia can now be considered stem cell disorders. Thus it should not be surprising that some acute leukemias share bilineage potential with CML and MDS. The phenotype of a particular leukemia is probably a function of the degree of differentiation allowed by the disease's leukemogenic changes. But the initial leukemogenic event is likely to occur inlow-quality, not high-quality, stem cells.High-quality stem cells generally appear to be resistant to leukemogenic changes. The duration of risk for therapy-related leukemia (10 years) may represent the life span of low-qualityhematopoietic stem cells.