Abstract

Telomeres are nucleprotein structures that cap the chromosomal ends, conferring genomic stability. Alterations in telomere maintenance and function are associated with tumorigenesis. In chronic lymphocytic leukemia (CLL), telomere length is an independent prognostic factor and short telomeres are associated with adverse outcome. Though telomere length associations have been suggested to be only a passive reflection of the cell’s replication history, here, based on published findings, we suggest a more dynamic role of telomere dysfunction in shaping the disease course. Different members of the shelterin complex, which form the telomere structure have deregulated expression and POT1 is recurrently mutated in about 3.5% of CLL. In addition, cases with short telomeres have higher telomerase (TERT) expression and activity. TERT activation and shelterin deregulation thus may be pivotal in maintaining the minimal telomere length necessary to sustain survival and proliferation of CLL cells. On the other hand, activation of DNA damage response and repair signaling at dysfunctional telomeres coupled with checkpoint deregulation, leads to terminal fusions and genomic complexity. In summary, multiple components of the telomere system are affected and they play an important role in CLL pathogenesis, progression, and clonal evolution. However, processes leading to shelterin deregulation as well as cell intrinsic and microenvironmental factors underlying TERT activation are poorly understood. The present review comprehensively summarizes the complex interplay of telomere dysfunction in CLL and underline the mechanisms that are yet to be deciphered.

Highlights

  • Telomeres are repetitive DNA sequences at the ends of the chromosomes that play a pivotal role in maintaining genomic stability by capping and protecting the ends from degradation and fusions

  • Since the restriction enzymes might not effectively digest the telomereassociated sequences (TAS) that are adjacent to the telomeres, the method usually overestimates the telomere length of a sample [22]

  • The presence of short telomere length was found to be significantly associated with various other poor prognostic clinical and genetic characteristics in chronic lymphocytic leukemia (CLL) which translates into an inferior survival compared to those with longer telomere length

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Summary

Telomere Dysfunction in Chronic Lymphocytic Leukemia

Reviewed by: Chris Pepper, Brighton and Sussex Medical School, United Kingdom Guru Prasad Maiti, Oklahoma Medical Research Foundation, United States. Different members of the shelterin complex, which form the telomere structure have deregulated expression and POT1 is recurrently mutated in about 3.5% of CLL. Cases with short telomeres have higher telomerase (TERT) expression and activity. TERT activation and shelterin deregulation may be pivotal in maintaining the minimal telomere length necessary to sustain survival and proliferation of CLL cells. Activation of DNA damage response and repair signaling at dysfunctional telomeres coupled with checkpoint deregulation, leads to terminal fusions and genomic complexity. Processes leading to shelterin deregulation as well as cell intrinsic and microenvironmental factors underlying TERT activation are poorly understood. The present review comprehensively summarizes the complex interplay of telomere dysfunction in CLL and underline the mechanisms that are yet to be deciphered

INTRODUCTION
TELOMERE DYSFUNCTION AND TUMORIGENESIS
METHODOLOGY FOR ANALYSIS OF TELOMERE LENGTH IN CLINICAL SAMPLES
TELOMERE LENGTH AND GENOMIC COMPLEXITY
TELOMERASE EXPRESSION AND ITS RELATION TO DISEASE FEATURES
TUMOR MICROENVIRONMENT AND TELOMERE DYSFUNCTION
TELOMERES AND TELOMERASE TARGETED CANCER THERAPIES
Findings
CONCLUSION
Full Text
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