Abstract
Background: We analyzed telomere maintenance mechanisms (TMMs) in lymph node samples from HL patients treated with standard therapy. The TMMs correlated with clinical outcomes of patients. Materials and Methods: Lymph node biopsies obtained from 38 HL patients and 24 patients with lymphadenitis were included in this study. Seven HL cell lines were used as in vitro models. Telomerase activity (TA) was assessed by TRAP assay and verified through hTERT immunofluorescence expression; alternative telomere lengthening (ALT) was also assessed, along with EBV status. Results: Both TA and ALT mechanisms were present in HL lymph nodes. Our findings were reproduced in HL cell lines. The highest levels of TA were expressed in CD30−/CD15− cells. Small cells were identified with ALT and TA. Hodgkin and Reed Sternberg cells contained high levels of PML bodies, but had very low hTERT expression. There was a significant correlation between overall survival (p < 10−3), event-free survival (p < 10−4), and freedom from progression (p < 10−3) and the presence of an ALT profile in lymph nodes of EBV+ patients. Conclusion: The presence of both types of TMMs in HL lymph nodes and in HL cell lines has not previously been reported. TMMs correlate with the treatment outcome of EBV+ HL patients.
Highlights
Hodgkin Lymphoma (HL) is a malignancy characterized by the presence of scarce malignant cells comprising only 1–2% of the total tumor burden
Telomerase activity (TA) was detected in all HL cell lines (Figure 1A) but relative TA levels varied between the cell lines (Figure 1B)
A high copy number of hTERT (5p15) was observed in 3/7 HL cell lines with high TA levels, which was associated with hTERT breakpoint rearrangements without amplification (Figure S1)
Summary
Hodgkin Lymphoma (HL) is a malignancy characterized by the presence of scarce malignant cells comprising only 1–2% of the total tumor burden. Telomere shortening in malignant cells and peripheral blood lymphocytes of HL patients has been documented [5,6,7]. This dysfunction requires the activation of a telomere maintenance mechanism (TMM) to support immortalization. Expression of the gene encoding telomerase is activated [8]. Previous studies have demonstrated the presence of telomerase activity (TA) and/or ALT mechanisms in various tumor types. We analyzed telomere maintenance mechanisms (TMMs) in lymph node samples from HL patients treated with standard therapy. Telomerase activity (TA) was assessed by TRAP assay and verified through hTERT immunofluorescence expression; alternative telomere lengthening (ALT) was assessed, along with EBV status. Results: Both TA and ALT mechanisms were present in HL lymph nodes
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