The identification of the leukemic stem cell, along with the desire to …

• Abstract
• Introduction
• The "End-Replication Problem" and Telomerase
• Telomere and Telomerase Biology in the Normal and Transplanted HSC Population
• Telomere Dysfunction in Hematopoietic Disease
• Telomerase and the Leukemic Stem Cell
• Acute Myeloid Leukemia and Myelodysplasia
• Chronic Myeloid Leukemia
• Conclusions and Future Directions
• References
• Figures
• Table

The most important prognostic factor in adult AML, as confirmedby the U.K. Medical Research Council (MRC) studies, are cytogeneticabnormalities at diagnosis [101]. However, considerable workhas been undertaken to determine whether telomerase activitycan further refine these prognostic data. Whether telomere shortening(with resulting genetic instability) might be involved in theevolution of these recurring genetic events is unknown but remainsunder consideration. The overall importance of telomerase inthe pathogenesis of AML has recently been confirmed by the demonstrationthat hTERT is necessary for growth of primary AML cells in amouse model [102]. A number of studies have investigated telomeraseactivity and telomere length in mononuclear cells (MNC) frompatients with MDS and AML [76, 103–105–108]. Telomereshortening was significantly more pronounced in patients withcytogenetic alterations as compared with patients with normalkaryotypes [100]. In this study, the shortest median telomerelength was found in the group with complex cytogenetic abnormalities.hTERT was overexpressed in patients with complex karyotypes,followed by patients with noncomplex karyotypes and patientswithout karyotypic changes [100]. This might suggest that withincreasing telomere attrition, by either replication-dependentor replication-independent mechanisms, karyotypic abnormalitiesbecomes more pronounced and, as a consequence, telomerase upregulationbecomes essential to prevent replicative senescence of the malignantclone. However, it has recently been suggested that telomeraseexpression in the context of short telomeres does not necessarilyprevent cells from reaching replicative exhaustion [109]. Whateverthe role of hTERT in determining the prognosis in AML, it isunlikely to surpass that of cytogenetics in discriminating riskgroups; recent work by our group on nearly 170 patients fromthe U.K. MRC AML12 trial has shown prognostic relevance of minorsignificance at best using quantitative polymerase chain reactionfor hTERT (N.E. Jordanides, W.N. Keith, R.K. Hills, K. Wheatley,Q.T. Luong, A.K. Burnett, T.L. Holyoake, M.W. Drummond, unpublishedobservations). In multivariate analysis, only cytogenetics andwhite 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].