Abstract
Leukocyte telomere length (TL) has been suggested as a marker of biological age in healthy individuals, but can also reflect inherited and acquired hematopoietic dysfunctions or indicate an increased turnover of the hematopoietic stem and progenitor cell compartment. In addition, TL is able to predict the response rate of tyrosine kinase inhibitor therapy in chronic myeloid leukemia (CML), indicates clinical outcomes in chronic lymphocytic leukemia (CLL), and can be used as screening tool for genetic sequencing of selected genes in patients with inherited bone marrow failure syndromes (BMFS). In tumor cells and clonal hematopoietic disorders, telomeres are continuously stabilized by reactivation of telomerase, which can selectively be targeted by telomerase-specific therapy. The use of the telomerase inhibitor Imetelstat in patients with essential thrombocythmia or myelofibrosis as well as the use of dendritic cell-based telomerase vaccination in AML patients with complete remissions are promising examples for anti-telomerase targeted strategies in hematologic malignancies. In contrast, the elevation in telomerase levels through treatment with androgens has become an exciting clinical intervention for patients with BMFS. Here, we review recent developments, which highlight the impact of telomeres and telomerase targeted therapies in hematologic dysfunctions.
Highlights
Telomeres consist of hundreds to thousands of repeated double strand hexanucleotides (in humans: (TTAGGG)n), a single-stranded overhang, as well as specific proteins that coat them [1,2]
When cells get critically short telomeres, replicative senescence precludes them from end to end fusions, enzymatic degradation, or nonreciprocal translocations that eventually result in chromosomal instability, aneuploidy, and tumorigenesis [6]
Real evidence for a contribution of telomere crisis and dysfunction to cancer progression can be found in chronic lymphocytic leukemia (CLL) [8] and myelodysplastic syndrome (MDS) [9], where the occurrence of critical short telomeres correlates with the presence of large-scale genomic rearrangements (CLL) and DNA damage (MDS), which are not detectable in samples with longer telomeres
Summary
Telomeres consist of hundreds to thousands of repeated double strand hexanucleotides (in humans: (TTAGGG)n), a single-stranded overhang, as well as specific proteins that coat them (telosome or shelterin protein complex) [1,2]. These findings further emphasize that in CML patients, BCR-ABL negative hematopoiesis is sustained by non-neoplastic HSPCs and argues against a substantial mean TL deficit in the normal, Ph− hematopoietic stem cell compartment It has been found, that in CML, TL analysis could indicate the severity of the disease and may provide important information for treatment decisions: when TL of newly diagnosed CML patients is evaluated before treatment, patients with the longest telomeres show a lower clinical risk profile in comparison to patients with shorter telomeres and may predict response to initial TKI therapy after 12 and 18 months according to ELN criteria [25].
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