Whether the mechanism of telomerase positivity in neoplasia
is expansion of a pre-existing telomerase-competent clone (i.e.,
the LSC population) or upregulation within clonal, previously
telomerase-negative cells (secondary to acquired genetic events)
remains unclear. Given the increasing evidence that many hematopoietic
malignancies arise in a stem or progenitor cell compartment,
the former hypothesis appears the more attractive. There are
few studies that have directly addressed telomerase biology
at the LSC level; the majority have used unselected leukemia
(or tumor) cell populations and therefore contain a heterogeneous
population of malignant and benign cells at various stages of
maturation. A case in point is CML, in which the progeny, as
detected in unselected PBL and BM, are largely postmitotic differentiated
cells in which telomerase is not expressed to any significant
degree. In these circumstances, studies performed on sorted
CD34
+BCR-ABL+ populations are the more relevant [
79]. We have
demonstrated subtly, but significantly, elevated TRAP levels
in this population; this elevation (as discussed above) is largely
explicable by differing cycling populations. Intriguingly, however,
expression of the major telomerase components was found to be
dysregulated, with a fivefold reduction in levels of hTR in
the clonal CD34
+ cells [
79]. Other groups have also found dysregulated
expression of telomerase components [
93] in this population.
One may therefore surmise, at least in early-phase tumorigenesis,
that a degree of telomerase dysfunction may accelerate telomere
loss. In later tumor stages, when telomere shortening begins
to exert selection pressure, telomerase-high (but telomere-short)
progenitor populations may predominate. This has been documented
during the progression of CML from chronic phase to blastic
phase (M.W. Drummond, unpublished observations; [
37] and reviewed
in [
77]). Similarly, in acute myeloid leukemia (AML), a hierarchy
of LSC organization and differentiation has been described [
94,
95], although studies on telomerase expression in this disorder
have largely used downstream blast populations and reported
widely varying degrees of telomerase expression. Such heterogeneity
at the stem and progenitor level may go some considerable way
in explaining the wide variation in telomerase expression, telomere
length, and changes during disease progression that have been
reported for AML [
96–
100], as discussed in more detail
below.
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