Telomere/telomerase interplay in virus‐driven and virus‐independent lymphomagenesis: pathogenic and clinical implications

Abstract

Telomerase is a ribonucleoprotein complex critically involved in extending and maintaining telomeres. Unlike the majority of somatic cells, in which hTERT and telomerase activity are generally silent, normal lymphocytes show transient physiological hTERT expression and telomerase activity according to their differentiation/activation status. During lymphomagenesis, induction of persistent telomerase expression and activity may occur before or after telomere shortening, as a consequence of the different mechanisms through which transforming factors/agents may activate telomerase. Available data indicate that the timing of telomerase activation may allow the distinction of two different lymphomagenetic models: (i) an early activation of telomerase via exogenous regulators of hTERT, along with an increased lymphocyte growth and a subsequent selection of cells with increased transforming potential may characterize several virus-related lymphoid malignancies; (ii) a progressive shortening of telomeres, leading to genetic instability which favors a subsequent activation of telomerase via endogenous regulators may occur in most virus-unrelated lymphoid tumors. These models may have clinically relevant implications, particularly for the tailoring of therapeutic strategies targeting telomerase.

hTERT Inhibition Triggers Epstein–Barr Virus Lytic Cycle and Apoptosis in Immortalized and Transformed B Cells: A Basis for New Therapies

“…Consistent with the notion that telomerase is involved in more cell processes than mere maintenance of telomere length (38), this study provides evidence that, besides inducing EBV lytic cycle, hTERT inhibition has antiproliferative and proapoptotic effects that may be of therapeutic importance. While hTERT inhibition in EBV-negative Burkitt's lymphoma cells induced accumulation of cells in G 0 -G 1 , as shown in other cell systems (39)(40)(41), infection of EBV-positive Burkitt's lymphoma cells with shTERT3.4 resulted in a marked increase of cells in the S-phase.…”

Double negative (CD19+IgG+IgD−CD27−) B lymphocytes: A new insight from telomerase in healthy elderly, in centenarian offspring and in Alzheimer's disease patients

“…cortisol [27], may compromise telomerase activity, while mitogenic stimulation, e.g. antigen stimulation for B lymphocytes [28], may induce it [29,30]. Thus, we detected the ability of DN B cells to reactivate telomerase by the engagement of both innate and adaptive immune receptors.…”

Role of miR-15a/miR-16-1 and the TP53 axis in regulating telomerase expression in chronic lymphocytic leukemia

“…TP53 alone may be inefficient in regulating TERT, since many other factors activate or repress TERT at a transcriptional level. 7 Our findings suggest that TP53 plays an important role in TERT regulation in 13q14del CLL, while in CLL with no or other chromosomal aberrations TERT may be regulated by other factors.…”

“…Telomerase expression, up-regulated in approximately 90% of human cancers, enables continuous and uncontrolled proliferation of the malignant cells driving tumor growth and progression. 7 Catalytic protein with telomere-specific reverse transcriptase activity (TERT) is the rate-limiting component of the telomerase complex, and its expression is correlated with telomerase activity. 8 We and others have shown that levels of TERT and its activity are prognostic markers in CLL.…”