The role of telomeres and telomerase in hematologic malignancies and hematopoietic stem cell transplantation

Abstract

Telomeres are specific nucleoprotein structures at the ends of eukaryotic chromosomes. Telomeres and telomere-associated proteins maintain genome stability by protecting the ends of chromosomes from fusion and degradation. In normal somatic cells, the length of the telomeres gradually becomes shortened with cell division. In tumor cells, the shortening of telomeres length is accelerated under the increased proliferation pressure. However, it will be maintained at an extremely short length as the result of activation of telomerase. Significantly shortened telomeres, activation of telomerase, and altered expression of telomere-associated proteins are common features of various hematologic malignancies and are related with progression or chemotherapy resistance in these diseases. In patients who have received hematopoietic stem cell transplantation (HSCT), the telomere length and the telomerase activity of the engrafted donor cells have a significant influence on HSCT outcomes. Transplantation-related factors should be taken into consideration because of their impacts on telomere homeostasis. As activation of telomerase is widespread in tumor cells, it has been employed as a target point in the treatment of neoplastic hematologic disorders. In this review, the characteristics and roles of telomeres and telomerase both in hematologic malignancies and in HSCT will be summarized. The current status of telomerase-targeted therapies utilized in the treatment of hematologic malignancies will also be reviewed.

Progressive telomere shortening is part of the natural history of chronic lymphocytic leukaemia and impacts clinical outcome: evidences from long term follow‐up

“…This is the first study on CLL focusing on TL dynamics on a large cohort of patients. This study shows that: (i) progressive telomere erosion occurs during the natural history of CLL and is higher than the YL described in healthy subjects (20-59 bp) (Wang et al, 2014); (ii) telomere loss is more pronounced when baseline TL is higher; (iii) accelerated telomere loss is associated with an inferior TFS, identifying a subgroup of patients that, despite a TL still far from critical levels, are likely to progress.…”

Correlation between telomere maintenance and stemness of mesenchymal stem/stromal cells

“…It is shown that cells from old donors or patients with telomerase deficiencies had limited replication ability, rendering the cell number necessary for HSCT insufficient [19] . Moreover, in patients who had received HSCT, the telomere length of engrafted stem cells is closely related to the outcomes of transplantation, thus highlighting the significance of telomere status during donor selection [20] . Therefore, some authors speculate about advantages of cord blood HSCs use, which are related to longer telomeres and higher replication ability than HSCs in bone marrow [19] .…”

Expressão do RNA telomérico não-codificante TERRA em leucemias agudas e telomeropatias

“…Como consequência, este conjunto de fatores pode levar à seleção de células anormais e progressão maligna (surgimento de neoplasias) ou à aplasia celular (telomeropatias) (BARTHEL et al, 2017). (HARTMANN et al, 2005;WANG et al, 2014;CHU et al, 2017). (KLAPPER et al, 2003).…”

“…AALBERS et al, 2013;EL BELBESY et al, 2015).Os telômeros são significativamente mais curtos nas células leucêmicas com citogenética anormal quando comparados àquelas sem anormalidade, sendo que os pacientes com cariótipos com múltiplas aberrações têm os telômeros mais curtos(CAPRARO et al, 2011). Além da citogenética, comprimento telomérico encurtado e aumento da atividade da telomerase também se correlacionam com a progressão da doença e recaída(WANG et al, 2014). LMA e LLA, a atividade da telomerase correlaciona-se com a expressão de TERT, e é maior no momento do diagnóstico ou progressão do que no momento da remissão(CAPRARO et al, 2011).…”

“…A indução de TERRA (em decorrência dos telômeros encurtados) auxiliaria as moléculas de telomerase posteriormente a atuar nos telômeros mais curtos, impedindo assim a senescência e morte destas células, apesar de sua rápida ciclagem(WATTS et al, 2016;LANSDORP, 2017;ROAKE;ARTANDI, 2017). Embora seja paradoxal, frequentemente encontram-se telômeros curtos e telomerase ativa em amostras de LMA (DEVILLE; HILLION; SÉGAL-BENDIRDJIAN, 2009;WANG et al, 2014). De maneira semelhante, explicaria os resultados de LLA, onde a expressão de TERRA mostrou-se diminuída e o comprimento telomérico encontrado nas amostras estudadas foi semelhante aos grupos saudáveis.…”