Differential Expression of Non-Shelterin Genes Associated with High Telomerase Levels and Telomere Shortening in Plasma Cell Disorders

Abstract

Telomerase, shelterin proteins and various interacting factors, named non-shelterin proteins, are involved in the regulation of telomere length (TL). Altered expression of any of these telomere-associated genes can lead to telomere dysfunction, causing genomic instability and disease development. In this study, we investigated the expression profile of a set of non-shelterin genes involved in essential processes such as replication (RPA1), DNA damage repair pathways (MRE11-RAD50-NBS1) and stabilization of telomerase complex (DKC1), in 35 patients with monoclonal gammopathy of undetermined significance (MGUS) and 40 cases with multiple myeloma (MM). Results were correlated with hTERT expression, TL and clinical parameters. Overall, a significant increase in DKC1, RAD50, MRE11, NBS1 and RPA1 expression along with an upregulation of hTERT in MM compared with MGUS was observed (p≤0.032). Interestingly, in both entities high mRNA levels of non-shelterin genes were associated with short TLs and increased hTERT expression. Significant differences were observed for DKC1 in MM (p ≤0.026), suggesting an important role for this gene in the maintenance of short telomeres by telomerase in myeloma plasma cells. With regard to clinical associations, we observed a significant increase in DKC1, RAD50, MRE11 and RPA1 expression in MM cases with high bone marrow infiltration (p≤0.03) and a tendency towards cases with advanced ISS stage, providing the first evidence of non-shelterin genes associated to risk factors in MM. Taken together, our findings bring new insights into the intricate mechanisms by which telomere-associated proteins collaborate in the maintenance of plasma cells immortalization and suggest a role for the upregulation of these genes in the progression of the disease.

Dysregulation of H/ACA ribonucleoprotein components in chronic lymphocytic leukemia

“…Simultaneously, we also observed increased DKC1 expression in patients with short TL, supporting the probable involvement of this gene in progressive telomere reduction, promoting genomic instability and immortalization of cancer cells. In concordance, a previous report [ 45 ] in lung cancer cells also found a strong association between Dyskerin and short telomeres and more recently our group showed DKC1 overexpression in MM patients with short TL [ 46 ]. In reference to GAR1 , we did not find association with the different prognostic factors evaluated.…”

Telomere protein complexes and their role in lymphoid malignancies

“…The expression profile of shelterin genes in plasma cell disorders have been extensively studied by our group (Table 1) (94,96,97). Our findings showed increased expression of shelterin components in MM compared to MGUS.…”

The MRE11–RAD50–NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair

“…Tel1 promotes MRX recruitment, whereas Rif2 acts as a negative regulator by enhancing ATP hydrolysis that opens Rad50, facilitating MRX release from DNA (184). In line with insights from yeast experiments, changes in expression and posttranslational modification of MRN and telomeric proteins are associated with various diseases in humans (185–187). In mouse embryonic fibro-blasts, the MRN complex is required for the response to telomere dysfunction, consistent with the idea that initiating this response shares common elements with the response to interstitial DNA damage (188).…”