Telomere Length and Hematological Disorders: A Review

Abstract

Telomeres compose the end portions of human chromosomes, and their main function is to protect the genome. In hematological disorders, telomeres are shortened, predisposing to genetic instability that may cause DNA damage and chromosomal rearrangements, inducing a poor clinical outcome. Studies from 2010 to 2019 were compiled and experimental studies using samples of patients diagnosed with hematological malignancies that reported the size of the telomeres were described. Abnormal telomere shortening is described in cancer, but in hematological neoplasms, telomeres are still shortened even after telomerase reactivation. In this study, we compared the sizes of telomeres in leukemias, myelodysplastic syndrome and lymphomas, identifying that the smallest telomeres are present in patients at relapse. In conclusion, the experimental and clinical data analyzed in this review demonstrate that excessive telomere shortening is present in major hematological malignancies and its analysis and measurement is a crucial step in determining patient prognosis, predicting disease risk and assisting in the decision for targeted therapeutic strategies.The word telomere originates from the Greek words τέλος (telos, end, extremity)+μέρος (meros, part), meaning "part of the extremity". The telomeres compose the end portions of chromosomes and consist of many 5'-TTAGGG-3' noncoding repeats (1).During a normal lifespan, telomeres naturally shorten. However, this can become a problem when excessive telomere shortening is observed in stem cells of both pediatric and adult patients. Healthy cells are predisposed to a division limit, also known as Hayflick limit, of 50 to 70 divisions before the cell undergoes senesce or apoptosis due to telomere attrition (2, 3).Short telomeres are associated with genetic instability, which may characterize them as a predisposition factor for hematological malignancies (4, 5). Human Telomeres and their FunctionsHuman telomeres are the end portions of chromosomes, which act primarily in DNA protection and genomic stability, preventing fusions and damage to the genetic material. Telomeres are composed of approximately 1000 to 2000 base pairs or 5-12 kb of non-coding TTAGGG repeats, which interacts with a group of proteins denominated as Shelterin complex (Figure 1) (3,(6)(7)(8).A major characteristic of telomeres is their progressive shortening that happens naturally with each division of somatic cells. The shortening occurs due to the DNA end replication problem, which consists of the inability of the cellular machinery to effectively synthesize the chromosomes ends during replication, alongside with the lack or insufficiency of pathways that promote telomere elongation, such as telomerase activity or the alternative lengthening of telomeres (ALT) (9-11).Telomere elongation occurs primarily by human telomerase (hTERT) activity, which is a ribonucleoprotein enzyme specialized in neutralizing telomeric DNA attrition by synthesizing new TTAGGG repeats at chromosome ends. This enzyme is composed by two subunits...

Methylation of Subtelomeric Chromatin Modifies the Expression of the lncRNA TERRA, Disturbing Telomere Homeostasis

“…hTERT expression is crucial for leukemia progression [ 21 , 34 , 35 , 36 , 37 ], so it was of interest for us to find an increase in the transcription of reverse transcriptase in the SC samples. When reactivation of telomerase transcription occurs, most of the 5p region is either amplified or involved in chromosomal rearrangements that facilitate the transcription of hTERT [ 34 , 38 , 39 , 40 ].…”

“…We selected the myelogenous lineage as our study model to take advantage of the stable telomeres that distinguish bone-marrow-derived neoplasias [ 21 ]. Since we intended to analyze telomeric stability, we compared the results obtained from expression analysis, telomere length measurement, and chromatin-mark enrichment between an untransformed cell line and a leukemia-derived cell line [ 22 ].…”

Telomerase (hTERT) Overexpression Reveals a Promising Prognostic Biomarker and Therapeutical Target in Different Clinical Subtypes of Pediatric Acute Lymphoblastic Leukaemia

“…However, despite all scientific data reports, further studies needs to evaluate and explore, if both, the size of the telomeres and the telomerase gene expression, may assist in the investigation of hematological malignancies, other types of cancer and several diseases, as well as establishing telomerase as a potent molecular biomarker for diagnosis, prognosis, and targeted therapy [10,68,69].…”

TERT genetic variability and telomere length as factors affecting survival and risk in acute myeloid leukaemia

“…AML it the most common haematological neoplasm associated with short telomeres 15 . The occurrence of telomere shortening in leukaemias depends particularly on telomerase activity, telomerase reverse transcriptase catalytic subunit ( TERT ) expression, TERT promoter gene mutation ( TERT p), and variability within the TERT gene 16 – 19 .…”