Spotlight on hTERT Complex Regulation in Cutaneous T-Cell Lymphomas.

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Telomerase is a key cancer hallmark, crucial for understanding carcinogenesis and therapeutic targeting.
• Primary cutaneous T-cell lymphomas (CTCL) exhibit telomerase dysregulation, yet data on its mechanisms remain limited.

Purpose of the Study:

• To investigate the mechanisms of telomerase transcriptional activation and activity regulation in CTCL.
• To explore the role of human telomerase reverse transcriptase (hTERT) gene polymorphisms and splicing in CTCL pathogenesis.

Main Methods:

• Analysis of 94 CTCL patients and 8 cell lines compared to 101 healthy controls.
• Genotyping of hTERT promoter and coding region single nucleotide polymorphisms (SNPs).
• Assessment of hTERT spliced transcript distribution and modulation using shRNAs.

Main Results:

• Specific hTERT promoter (rs2735940, rs2853672) and coding (rs2853676) SNPs are associated with CTCL occurrence.
• CTCL cells show an increased proportion of hTERT β+ variants, indicating altered post-transcriptional regulation.
• Reducing the α-β+ hTERT transcript variant decreased proliferation and tumorigenicity in T-MF cells in vitro.

Conclusions:

• Post-transcriptional regulation of telomerase, particularly hTERT splicing, plays a significant role in CTCL lymphomagenesis.
• The α-β+ hTERT transcript variant may have a novel role in CTCL development and progression.
• Targeting hTERT splicing represents a potential therapeutic strategy for CTCL.