Frontiers in Clinical Drug Research - Anti-Cancer Agents

Volume: 1

Indexed in: EBSCO.

Frontiers in Clinical Drug Research - Anti-Cancer Agents should prove to be a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critical information for ...
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The Mechanisms of Telomere and Telomerase Regulation in Hematologic Malignancies

Pp. 115-183 (69)

Kiyotaka Kawauchi, Masaharu Akiyama and Osamu Yamada

Abstract

Human chromosome ends are capped by telomeric DNA composed of long arrays of (TTAGGG)n repeats. During each cell division, telomeric DNA is shortened by 50-100 bp. This attenuation of chromosome ends results in a loss of coding sequences and end-to-end chromosomal fusions, leading to chromosomal instability and aberrations. Therefore, telomere shortening is a critical event that acts as a mitotic clock to measure cellular life span. Telomerase, a ribonucleoprotein composed of a catalytic subunit (TERT), an RNA template (TERC), and the dyskerin protein, elongates telomeric sequences in germ cells and immature precursors such as hematopoietic stem cells. Telomerase is activated by multiple signaling pathways and its activity is regulated at the levels of gene transcription and translation, as well as post-translational modifications, trafficking, and assembly of the protein. Telomerase is upregulated in most cancer cells, including hematologic malignancies. Telomere shortening and telomerase activation are correlated with the prognosis and aggressiveness of various hematologic tumors. Therefore, targeting telomerase may be an attractive therapeutic strategy for hematologic malignancies. In fact, several strategies of telomerase inhibition, such as G-quadruplex-interacting agents, catalytic/reverse transcriptase inhibitors, oligonucleotides, and immunotherapy, have been developed as therapeutic methods.

Keywords:

Acute leukemia, chronic leukemia, hematologic malignancies, malignant lymphoma, multiple myeloma, regulation mechanism, shelterin complex, signal transduction, telomerase, telomerase inhibitor, telomere.

Affiliation:

Tokyo Women’s Medical University, Medical Center East, Department of Medicine, Tokyo, Japan; Nishiogu Clinic, Tokyo, Japan.