Telomeres and telomerase in chronic myeloid leukaemia: impact for pathogenesis, disease progression and targeted therapy

Abstract

Telomeres are specialized structures localized at the end of human chromosomes. Due to the end replication problem, each cell division results in a loss of telomeric repeats in normal somatic cells. In germ line and stem cells, the multicomponent enzyme telomerase maintains the length of telomere repeats. However, elevated telomerase activity has also been reported in the majority of solid tumours as well as in acute and chronic leukaemia. Chronic myeloid leukaemia (CML) serves as a model disease to study telomere biology in clonal myeloproliferative disorders. In CML, telomere shortening correlates with disease stage, duration of chronic phase (CP), prognosis measured by the Hasford risk score and the response to disease-modifying therapeutics such as the tyrosine kinase inhibitor Imatinib. In addition, telomerase activity (TA) is already increased in CP CML and further upregulated with disease progression to accelerated phase and blast crisis (BC). Furthermore, a correlation of TA with increased genetic instability as well as a shorter survival of the patients has been reported. Here, we review the current state of knowledge of the role of telomere and telomerase biology in CML and discuss the possible impact of novel treatment approaches.

Telomere loss in Philadelphia-negative hematopoiesis after successful treatment of chronic myeloid leukemia: Evidence for premature aging of the myeloid compartment

“…These cells also have shorter telomeres compared to healthy cells as frequently occur in human malignancies (Keller et al, 2009). Severe telomere shortening has additionally been associated with progression into blast crisis (Keller et al, 2009;Boultwood et al, 2000). Conversely, the achievement of CCyR after successful treatment has been associated with BM repopulation by Ph-negative hematopoietic cells characterized by longer telomeres compared to CML cells (Brü mmendorf et al, 2003).…”

“…Telomere erosion has been extensively investigated in Ph-positive CML cells as well (Keller et al, 2009). These cells also have shorter telomeres compared to healthy cells as frequently occur in human malignancies (Keller et al, 2009). Severe telomere shortening has additionally been associated with progression into blast crisis (Keller et al, 2009;Boultwood et al, 2000).…”

“…Telomere erosion has been extensively investigated in Ph-positive CML cells as well (Keller et al, 2009). These cells also have shorter telomeres compared to healthy cells as frequently occur in human malignancies (Keller et al, 2009).…”

Which has greater effects on leukomogenesis in Philadelphia chromosome positive leukemias: fusion or cell type?

“…Although the relation between telomerase and BCR-ABL fusion proteins could not be explained exactly, a combination of tyrosine kinase inhibitors with telomerase inhibitors has been suggested as an attractive therapy for CML patients [40].…”

MDS shows a higher expression of hTERT and alternative splice variants in unactivated T-cells

“…In most cancer cells, telomerase activity is up-regulated to maintain telomere length related to cell immortality [5]. The level of telomerase activity might also be of prognostic relevance [8, 9]. In MDS, the T-cells are characterized by skewed repertoire distribution and form suppressive lymphoid aggregates within the bone marrow of some patients where they can directly suppress hematopoiesis [10, 11].…”