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

Biology Articles » Cell biology » Concise Review: Telomere Biology in Normal and Leukemic Hematopoietic Stem Cells » Chronic Myeloid Leukemia

Chronic Myeloid Leukemia

- Concise Review: Telomere Biology in Normal and Leukemic Hematopoietic Stem Cells

In terms of telomere and telomerase biology, CML is arguablythe best characterized of human malignancies. A number of factorssingle it out as an ideal model for such studies. First, themalignant HSC (as defined by the presence of the BCR-ABL translocation)are characterized by increased cellular turnover (comprehensivelyreviewed in [112]). Second, the disease is characterized clinicallyby a relatively stable chronic phase (CP) that can last formany years. Third, progression to the accelerated phase or toblastic phase (BP) of the disease is associated with increasedgenetic instability and with the acquisition of additional cytogeneticabnormalities and mutations that are responsible for the alteredand more aggressive growth pattern of the malignant clone (Fig. 2).To investigate the impact of telomere biology on disease progressionin malignant HSC in this disease, we comparatively analyzedtelomere length in BCR-ABL⁺ PBL and BCR-ABL^– (i.e., polyclonal)T lymphocytes, respectively. We found that telomeres in malignantcells were indeed significantly shorter than BCR-ABL^–T lymphocytes [75]. Successful therapy with the tyrosine kinaseinhibitor imatinib mesylate was associated with an increasein mean telomere length as polyclonal hematopoiesis was restored[113, 114]. Furthermore, age-adjusted telomere shortening wasfound to be correlated with disease stage, remaining durationof CP before onset of BP [75], and Hasford risk score [37].A number of studies have confirmed ongoing telomere shorteningin the context of CML progression (Table 1); however, the roleof telomerase is less certain. Our studies on CD34⁺-selected,BCR-ABL⁺ (>90%) primary LSC as described above suggest thatany elevation in whole population telomerase activity (as measuredby the TRAP assay) is due to an increased proportion of cyclingprogenitors. Indeed, at an individual LSC level, it is possiblethat the major telomerase components hTR and hTERT are dysregulated[79, 93]. It is therefore not surprising that telomere lossoccurs; indeed, it may be accelerated to 10–20 times thenormal rate, as measured in leukemic PBL [37]. Contributoryfactors, over and above replication and dysregulation of telomerase-inducedattrition, include oxidative damage to telomere sequence witheventual loss. Interestingly, the BCR-ABL fusion protein significantlyincreased generation of reactive oxygen species in transfectedcells [115] and is one potential mechanism linking ongoing geneticdamage, clonal evolution, and telomere loss during CML progressionfrom CP. Furthermore, oxidative stress would appear to resultin translocation of endogenous hTERT out of the nucleus andinto the cytosol, in a process that left overall TRAP activityunchanged [116]. It is therefore important to stress once againthat TRAP activity is not synonymous with telomere maintenance.