Abstract
In this study, we explored changes in the expression of the telomere maintenance genes, TRF1, TRF2 and TANK1 in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Results were correlated with human telomerase reverse transcriptase (hTERT ) expression, telomere length (TL) and clinicopathological characteristics. Bone marrow (BM) samples from 132 patients, 64 with MGUS and 68 with MM, were studied. Real-time quantitative reverse transcription-polymerase chain reaction was used to quantify gene expression. TL was evaluated by terminal restriction fragment length analysis. MGUS patients showed increased TRF1 levels (P = 0.006) and lower expression of TRF2 (P = 0.005) and TANK1 (P = 0.003) compared with MM patients. For hTERT analysis, patients were divided into three groups by use of receiver operating characteristics: low (group I [GI]), intermediate (group II [GII]) and high (group III [GIII]) expression. We observed increasing expression of TRF2 and TANK1 from GI to GIII in MGUS and MM, with differences for both genes in MM (P < 0.01) and for TRF2 in MGUS (P < 0.01). GIII patients with the highest telomerase expression had the shortest TL. In both entities, a positive association between TRF2-TANK1, TRF2-hTERT and TANK1-hTERT (P ≤ 0.01) was observed. In MM, the percentage of BM infiltration and Ki-67 index were positively associated with TRF2, TANK1 and hTERT expression (P ≤ 0.03) and negatively with TL (P = 0.02), whereas lactate dehydrogenase was significantly correlated with TRF2 mRNA (P = 0.008). Our findings provide the first evidence of a modification in the expression of telomeric proteins in plasma cell disorders, and suggest that mechanisms other than telomerase activation are involved in TL maintenance in these pathologies.
Highlights
Monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) are the two most common plasma cell disorders characterized by the presence of clonal bone marrow (BM) plasma cells and of a monoclonal protein in serum and/or urine
The mRNA expression of TRF1, TRF2, TANK1 and human telomerase reverse transcriptase (hTERT) was evaluated in 64 patients with MGUS and 68 with MM
The evaluation of remaining genes according to hTERT groups showed an increased expression of TRF2 and TANK1 from GI to GIII in MGUS and MM
Summary
Monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) are the two most common plasma cell disorders characterized by the presence of clonal bone marrow (BM) plasma cells and of a monoclonal protein in serum and/or urine. MGUS is characterized by serum M protein levels less than 3 mg/dL, BM plasma cell infiltration (BMPCI) less than 10% and no clinical manifestations related to monoclonal gammopathy [2]. This entity is one of the most common premalignant disorders in Western countries, with a prevalence of 3.2% in the population of white individuals age 50 years and older. Recent studies have identified markers that can be used to identify patients with high risk of progression: higher levels of monoclonal protein, non-IgG protein isotype and abnormal ratio of free light chains [3]
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