MDS shows a higher expression of hTERT and alternative splice variants in unactivated T-cells

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.

The prognostic significance of global aberrant alternative splicing in patients with myelodysplastic syndrome

“…Some splicing variants of specific genes have been proposed to serve as diagnostic or prognostic biomarkers for cancer patients 27 , 28 . Although aberrant AS of specific genes has been reported in MDS, the global pattern of splicing in this disease has not been well explored 29 – 32 .…”

TERT—Regulation and Roles in Cancer Formation

“…TERT regulation is a multifarious process, which involves not only the transcriptional mechanisms described in the previous sections, but also posttranscriptional ones. This includes pre-mRNA alternative splicing of the TERT gene ( 161 – 163 ). There as many as 22 potential alternative splicing sites in the TERT gene, but the function of many of them is unclear ( 164 – 168 ).…”

Telomerase‐based therapies in haematological malignancies

“…In MDS patients, TL was shorter than healthy controls in isolated peripheral blood mononuclear cells, CD15 + myeloid cells, peripheral blood granulocytes, CD19 + lymphocytes, bone marrow, peripheral blood leukocytes and/or CD34 + stem cells 87 . Although TA and hTERT mRNA increased significantly in the MDS clone derived from myeloid precursors, hTERT deficiency caused the inhibition of T lymphocyte differentiation and loss of naïve T‐cells 88,89 . Park et al 2017, measured TLs changes with Q‐Fish and TA by real‐time quantitative PCR in quiescent (interphase) and proliferating (metaphase) cells of MDS patients.…”