Abstract
Telomere instability and telomerase reactivation are believed to play an important role in the development of myelodysplastic syndromes (MDS). Abnormal enzymatic activity of human telomerase reverse transcriptase (hTERT), and its alternative splice variants have been reported to account for deregulated telomerase function in many cancers. In this study, we aim to compare the differences in expression of hTERT and hTERT splice variants, as well as telomere length and telomerase activity in unstimulated T-cells between MDS subgroups and healthy controls. Telomere length in MDS cases was significantly shorter than controls (n = 20, p<0.001) and observed across all subtypes of MDS using World Health Organization classification (WHO subgroups versus control: RARS, p= 0.009; RCMD, p=0.0002; RAEB1/2, p=0.004, respectively) and the International Prognostic Scoring System (IPSS subgroups: Low+Int-1, p<0.001; Int-2+High, p=0.004). However, unstimulated T-cells from MDS patients (n=20) had significantly higher telomerase activity (p=0.002), higher total hTERT mRNA levels (p=0.001) and hTERT α+β- splice variant expression (p<0.001) compared to controls. Other hTERT splice variants were lower in expression and not significantly different among cases and controls. Telomerase activity was positively correlated with total hTERT levels in MDS (r=0.58, p=0.007). This data is in sharp contrast to data published previously by our group showing a reduction in telomerase and hTERT mRNA in MDS T-cells after activation. In conclusion, this study provides additional insight into hTERT transcript patterns and activity in peripheral T-cells of MDS patients. Additional studies are necessary to better understand the role of this pathway in MDS development and progression.
Highlights
myelodysplastic syndromes (MDS) represents a diverse group of clonal disorders characterized by impaired proliferation and differentiation of hematopoietic stem cells or progenitor cells, dysplastic morphology, ineffective haematopoiesis, and an elevated risk of progression into acute myeloid leukemia (AML) [1]
Comparing the T-cells from MDS cases and controls, we observed a significant increase in telomerase activity in cases as shown in Figure 2a (p = 0.002)
Further analysis showed no significant differences in T-cell telomerase activity among different patient subgroups (WHO: p = 0.7631;International Prognostic Scoring System (IPSS): p = 0.4278, Table 2) and significantly higher enzymatic activity in all subgroups compared to controls
Summary
MDS represents a diverse group of clonal disorders characterized by impaired proliferation and differentiation of hematopoietic stem cells or progenitor cells, dysplastic morphology, ineffective haematopoiesis, and an elevated risk of progression into acute myeloid leukemia (AML) [1]. Telomeres are a repetitive hexanucleotide (TTAGGG) region that protect from chromosomal deterioration [4]. Telomerase activity is limited in the germ line, activated lymphocytes and some types of stem cells [6, 7]. Telomerase activity is up-regulated to maintain telomere length related to cell immortality [5]. In MDS, the T-cells are characterized by skewed repertoire distribution and form suppressive lymphoid aggregates within the bone marrow of some patients where they can directly suppress hematopoiesis [10, 11]
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