Blood, 15 June 2001, Vol. 97, No. 12, pp. 3681-3682
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-quality for 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 in
low-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-quality
hematopoietic stem cells.
Richard J. Jones
Johns Hopkins Oncology
Center
