The most important prognostic factor in adult AML, as confirmed
by the U.K. Medical Research Council (MRC) studies, are cytogenetic
abnormalities at diagnosis [
101]. However, considerable work
has been undertaken to determine whether telomerase activity
can further refine these prognostic data. Whether telomere shortening
(with resulting genetic instability) might be involved in the
evolution of these recurring genetic events is unknown but remains
under consideration. The overall importance of telomerase in
the pathogenesis of AML has recently been confirmed by the demonstration
that hTERT is necessary for growth of primary AML cells in a
mouse model [
102]. A number of studies have investigated telomerase
activity and telomere length in mononuclear cells (MNC) from
patients with MDS and AML [
76,
103–
105–
108]. Telomere
shortening was significantly more pronounced in patients with
cytogenetic alterations as compared with patients with normal
karyotypes [
100]. In this study, the shortest median telomere
length was found in the group with complex cytogenetic abnormalities.
hTERT was overexpressed in patients with complex karyotypes,
followed by patients with noncomplex karyotypes and patients
without karyotypic changes [
100]. This might suggest that with
increasing telomere attrition, by either replication-dependent
or replication-independent mechanisms, karyotypic abnormalities
becomes more pronounced and, as a consequence, telomerase upregulation
becomes essential to prevent replicative senescence of the malignant
clone. However, it has recently been suggested that telomerase
expression in the context of short telomeres does not necessarily
prevent cells from reaching replicative exhaustion [
109]. Whatever
the role of hTERT in determining the prognosis in AML, it is
unlikely to surpass that of cytogenetics in discriminating risk
groups; recent work by our group on nearly 170 patients from
the U.K. MRC AML12 trial has shown prognostic relevance of minor
significance at best using quantitative polymerase chain reaction
for hTERT (N.E. Jordanides, W.N. Keith, R.K. Hills, K. Wheatley,
Q.T. Luong, A.K. Burnett, T.L. Holyoake, M.W. Drummond, unpublished
observations). In multivariate analysis, only cytogenetics and
white count at diagnosis remained significant.
Because of the uneven distribution of telomere length on individualchromosome arms [36], critical shortening of telomeres on particularchromosomes could promote the formation of chromosomal aberrationsand contribute to clonal evolution. This hypothesis remainsrelevant even if the average telomere length remains well abovethe critical level of shortening [110]. Distinct groups of AMLthat are characterized either by aberrations that could resultfrom telomere dysfunction (terminal deletions, gains/lossesof chromosome parts, or nonreciprocal translocations) or byaberrations that are unlikely to result from telomere dysfunction(e.g., reciprocal translocations or inversions) could serveas an ideal model to study the effect of telomere shorteningand telomerase activity during tumorigenesis [111].
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