Dysregulation of Telomere Lengths and Telomerase Activity in Myelodysplastic Syndrome

Park, Hee Sue; Choi, Jin Won; See, Cha Ja; Kim, Jung Ah; Park, Si Nae; Im, Kyongok; Kim, Sung Min; Lee, Dong Hoon; Hwang, Sang Mee

doi:10.3343/alm.2017.37.3.195

Cited by 27 publications

(24 citation statements)

References 25 publications

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“…In a recent study [ 72 ], no significant correlation between telomerase activity and TL could be found in MDS patients ( n = 53), and for overall survival, there was no significant difference between high and low telomerase activity according to the log rank method. However, patients with high telomerase activity showed a significantly shorter interval for transformation to acute leukemia ( p = 0.010), suggesting high telomerase activity as a poor prognostic marker in MDS.…”

Section: Myelodysplastic Syndrome (Mds)mentioning

confidence: 96%

Telomeres and Telomerase in Hematopoietic Dysfunction: Prognostic Implications and Pharmacological Interventions

Vasko

Kaifie

Stope

et al. 2017

IJMS

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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.

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Section: Myelodysplastic Syndrome (Mds)mentioning

confidence: 96%

Telomeres and Telomerase in Hematopoietic Dysfunction: Prognostic Implications and Pharmacological Interventions

Vasko

Kaifie

Stope

et al. 2017

IJMS

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“…Other cancers for which short telomere length can be used as a prognostic indicator include non-small-cell lung cancer, myelodysplastic syndromes (MDS) and multiple myeloma [ 127 , 128 , 129 , 130 ]. This finding was particularly striking in Multiple Myeloma, considering median telomere length was measured from a mixed population of cells extracted from bone marrow [ 129 ].…”

Section: Telomere Length As a Prognostic Marker In Cancermentioning

confidence: 99%

Telomere Length Dynamics and the Evolution of Cancer Genome Architecture

Cleal

Norris

Baird

2018

IJMS

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Telomeres are progressively eroded during repeated rounds of cell division due to the end replication problem but also undergo additional more substantial stochastic shortening events. In most cases, shortened telomeres induce a cell-cycle arrest or trigger apoptosis, although for those cells that bypass such signals during tumour progression, a critical length threshold is reached at which telomere dysfunction may ensue. Dysfunction of the telomere nucleoprotein complex can expose free chromosome ends to the DNA double-strand break (DSB) repair machinery, leading to telomere fusion with both telomeric and non-telomeric loci. The consequences of telomere fusions in promoting genome instability have long been appreciated through the breakage–fusion–bridge (BFB) cycle mechanism, although recent studies using high-throughput sequencing technologies have uncovered evidence of involvement in a wider spectrum of genomic rearrangements including chromothripsis. A critical step in cancer progression is the transition of a clone to immortality, through the stabilisation of the telomere repeat array. This can be achieved via the reactivation of telomerase, or the induction of the alternative lengthening of telomeres (ALT) pathway. Whilst telomere dysfunction may promote genome instability and tumour progression, by limiting the replicative potential of a cell and enforcing senescence, telomere shortening can act as a tumour suppressor mechanism. However, the burden of senescent cells has also been implicated as a driver of ageing and age-related pathology, and in the promotion of cancer through inflammatory signalling. Considering the critical role of telomere length in governing cancer biology, we review questions related to the prognostic value of studying the dynamics of telomere shortening and fusion, and discuss mechanisms and consequences of telomere-induced genome rearrangements.

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“…Furthermore, it is very labor-intensive to generate a sufficient number of karyograms for measurements and there may be a selection bias with respect to the cell types that are mitotically active in the sample. These types of problems can be overcome by quantitative fluorescence in situ hybridization of interphase nuclei (iQFISH) measuring relative telomere content in interphase nuclei [ 22 ]. We have previously utilized this T/C iQFISH method to investigate telomeres in a patient’s bone marrow cells with or without genomic aberrations in the same sample [ 20 ].…”

Section: Resultsmentioning

confidence: 99%

“…The bone marrow sample of Case 2 and the age-matched control were hybridized with a Cy3-labeled PNA telomere probe and an FITC-labeled PNA centromere 2 probe. Images of at least 250 nuclei in each case were captured automatically and analyzed by the ISIS-Telomere module [ 19 , 22 ]. The software calculates a relative telomere to centromere (T/C) fluorescence ratio unit (FRU) multiplied by 100 [ 19 , 20 ].…”

Section: Resultsmentioning

confidence: 99%

Telomere Shortening in Hematological Malignancies with Tetraploidization—A Mechanism for Chromosomal Instability?

Kjeldsen

2017

Cancers

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Aneuploidy, the presence of an abnormal number of chromosomes in a cell, is one of the most obvious differences between normal and cancer cells. There is, however, debate on how aneuploid cells arise and whether or not they are a cause or a consequence of tumorigenesis. Further, it is important to distinguish aneuploidy (the “state” of the karyotype) from chromosomal instability (CIN; the “rate” of karyotypic change). Although CIN leads to aneuploidy, not all aneuploid cells exhibit CIN. One proposed route to aneuploid cells is through an unstable tetraploid intermediate because tetraploidy promotes chromosomal aberrations and tumorigenesis. Tetraploidy or near-tetraploidy (T/NT) (81–103 chromosomes) karyotypes with or without additional structural abnormalities have been reported in acute leukemia, T-cell and B-cell lymphomas, and solid tumors. In solid tumors it has been shown that tetraploidization can occur in response to loss of telomere protection in the early stages of tumorigenesis in colon cancer, Barrett’s esophagus, and breast and cervical cancers. In hematological malignancies T/NT karyotypes are rare and the role of telomere dysfunction for the induction of tetraploidization is less well characterized. To further our understanding of possible telomere dysfunction as a mechanism for tetrapolydization in hematological cancers we here characterized the chromosomal complement and measured the telomere content by interphase nuclei quantitative fluorescence in situ hybridization (iQFISH) in seven hematological cancer patients with T/NT karyotypes, and after cytogenetic remission. The patients were identified after a search in our local cytogenetic registry in the 5-year period between June 2012 and May 2017 among more than 12,000 analyzed adult patients in this period. One advantage of measuring telomere content by iQFISH is that it is a single-cell analysis so that the telomere content can be distinguished between normal karyotype cells and cells with T/NT karyotypes. We find that the telomeres are particularly short in cells with T/NT karyotypes as compared with normal cells, and in T/NT karyotypes harboring additional chromosomal aberrations as well. These findings suggest that telomere dysfunction in hematological malignancies may be a mechanism for tetraploidization and CIN.

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Dysregulation of Telomere Lengths and Telomerase Activity in Myelodysplastic Syndrome

Cited by 27 publications

References 25 publications

Telomeres and Telomerase in Hematopoietic Dysfunction: Prognostic Implications and Pharmacological Interventions

Telomeres and Telomerase in Hematopoietic Dysfunction: Prognostic Implications and Pharmacological Interventions

Telomere Length Dynamics and the Evolution of Cancer Genome Architecture

Telomere Shortening in Hematological Malignancies with Tetraploidization—A Mechanism for Chromosomal Instability?

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