Spotlight on hTERT Complex Regulation in Cutaneous T-Cell Lymphomas
Abstract
:1. Introduction
2. Methods
2.1. Patients and Healthy Controls
2.2. CTCL Cell Lines
2.3. Telomerase Activity Estimation
2.4. Nucleic Acid Isolation
2.5. Telomere Length Measurement
2.6. hTERT Hotspot Promoter Mutations Detection
2.7. hTERT SNPs Genotyping
2.8. hTERT Splicing Variants Expression
2.9. Lentiviral shRNA Construction and Production
2.10. Lentiviral Cell Transduction
2.11. Cell Proliferation Analysis
2.12. Cell Clonogenicity Analysis
2.13. Statistical Analysis
3. Results
3.1. hTERT SNPs Are Associated with CTCL Risk in Patient Cells
3.2. hTERT Transcription Regulation in CTCL: hTERT Promoter Mutations Are a Rare Event in CTCL Patients
3.3. hTERT Post-Transcription Regulation in CTCL Cells
3.3.1. hTERT Is Subjected to Alternative Splicing in CTCL Cells
3.3.2. Modulation of RT Domain Transcriptome
3.3.3. Modulation of hTERT Transcriptome Affects Telomerase Non-Canonical Functions
4. Discussion
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Locus/Genotype | Cell Lines n (%) | Controls n (%) | Patients n (%) | OR (95% CI) | p-Value |
---|---|---|---|---|---|
rs2735940 | n = 8 | n = 101 | n = 66 | ||
TT | 2 (25) | 40 (39.6) | 11 (16.7) | 1.00 a | |
TC | 6 (75) | 48 (47.5) | 39 (59.1) | 3.00 (1.31–6.89) | 0.010 |
CC | 0 | 13 (12.9) | 16 (24.2) | 3.79 (1.35–10.6) | 0.011 |
Dominant model (C carrier vs. TT b) | 61 (60.4)/11 (39.6) | 55 (83.3)/11 (16.7) | 3.20 (1.44–7.08) | 0.004 | |
rs2853669 | n = 8 | n = 96 | n = 66 | ||
TT | 0 | 40 (41.7) | 28 (42.4) | 1.00 a | |
TC | 8 (100) | 42 (43.7) | 29 (43.9) | 0.84 (0.41–1.75) | 0.649 |
CC | 0 | 14 (14.6) | 9 (13.6) | 0.80 (0.29–2.21) | 0.660 |
Dominant model (C carrier vs. TT b) | 56 (58.3)/40 (41.7) | 38 (57.6)/28 (42.4) | 0.83 (0.42–1.64) | 0.595 | |
rs2853672 | n = 8 | n = 101 | n = 66 | ||
GG | 2 (25) | 38 (37.6) | 16 (24.2) | 1.00 a | |
GT | 6 (75) | 50 (49.5) | 38 (57.6) | 2.04 (0.94–4.44) | 0.069 |
TT | 0 | 13 (12.9) | 12 (18.2) | 2.67 (0.94–7.62) | 0.063 |
Dominant model (T carrier vs. GG b) | 63 (62.4)/38 (37.6) | 50 (75.8)/16 (24.2) | 2.18 (1.04–4.58) | 0.039 | |
rs2853676 | n = 8 | n = 101 | n = 66 | ||
GG | 4 (50) | 47 (46.5) | 40 (40.6) | 1.00 a | |
AG | 3 (37.5) | 42 (41.6) | 26 (39.4) | 0.59 (0.29–1.19) | 0.141 |
AA | 1 (12.5) | 12 (11.9) | 0 | 0.00 | 0.999 |
Dominant model (A carrier vs. GG b) | 54 (53.5)/47 (46.5) | 26 (39.4)/40 (60.6) | 0.46 (0.23–0.92) | 0.028 | |
rs10069690 | n = 8 | n = 101 | n = 66 | ||
CC | 0 | 50 (49.5) | 36 (54.5) | 1.00 a | |
CT | 8 (100) | 38 (37.6) | 29 (43.9) | 1.28 (0.64–2.57) | 0.479 |
TT | 0 | 13 (12.9) | 1 (1.5) | 0.14 (0.017–1.21) | 0.074 |
Dominant model (T carrier vs. CC b) | 51 (50.5)/50 (49.5) | 30 (45.5)/36 (54.5) | 1.02 (0.52–1.98) | 0.963 |
Mutation Rate (%) | Mutation | |
---|---|---|
Patients | 1/67 (1.5%) | |
LPDs | 0/18 (0%) | - |
cALCL | 0/10 (0%) | - |
LyP | 0/8 (0%) | - |
MF | 0/32 (0%) | - |
MF | 0/24 (0%) | - |
T-MF | 0/8 (0%) | - |
SS | 1/17 (5.9%) | −146 C > T |
Cell lines | 1/8 (12.5%) | |
cALCL | 0/4 (0%) | - |
T-MF | 1/1 (100%) | −146 C > T |
SS | 0/3 (0%) | - |
Cells | Total hTERT Transcripts (Sum of α+β+, α−β+, and α+β−) | α+β+ | α−β+ | α+β− |
---|---|---|---|---|
% (p-Value) | % (p Value) | |||
Mac1 | 100 | 22.8 | 8.0 | 69.2 |
Mac2A | 100 (0.0022) | 63.2 (0.5887) | 5.9 (0.0022) | 30.9 (0.0022) |
Mac2B | 100 (0.0260) | 70.5 (0.1667) | 12.0 (0.0628) | 17.5 (0.0022) |
Healthy controls | 100 | 2.9 | 0.0 | 97.1 |
SS patients | 100 (0.0120) | 35.0 (0.2507) | 4.9 (0.0050) | 60.1 (0.0290) |
Cells | Total hTERT Transcripts (Sum of α+β+, α−β+ and α+β−) | α+β+ | α−β+ | α+β− |
---|---|---|---|---|
% (p Value) | % (p Value) | |||
shControl | 50.9 | 9.9 | 39.2 | |
sh1 | 100 (0.1797) | 48.3 (0.4857) | 17.7 (0.0237) | 34 (0.2196) |
sh2 | 100 (0.1797) | 54.5 (0.9448) | 5.5 (0.0003) | 40 (0.7255) |
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Ropio, J.; Prochazkova-Carlotti, M.; Batista, R.; Pestana, A.; Chebly, A.; Ferrer, J.; Idrissi, Y.; Cappellen, D.; Durães, C.; Boaventura, P.; et al. Spotlight on hTERT Complex Regulation in Cutaneous T-Cell Lymphomas. Genes 2023, 14, 439. https://doi.org/10.3390/genes14020439
Ropio J, Prochazkova-Carlotti M, Batista R, Pestana A, Chebly A, Ferrer J, Idrissi Y, Cappellen D, Durães C, Boaventura P, et al. Spotlight on hTERT Complex Regulation in Cutaneous T-Cell Lymphomas. Genes. 2023; 14(2):439. https://doi.org/10.3390/genes14020439
Chicago/Turabian StyleRopio, Joana, Martina Prochazkova-Carlotti, Rui Batista, Ana Pestana, Alain Chebly, Jacky Ferrer, Yamina Idrissi, David Cappellen, Cecília Durães, Paula Boaventura, and et al. 2023. "Spotlight on hTERT Complex Regulation in Cutaneous T-Cell Lymphomas" Genes 14, no. 2: 439. https://doi.org/10.3390/genes14020439
APA StyleRopio, J., Prochazkova-Carlotti, M., Batista, R., Pestana, A., Chebly, A., Ferrer, J., Idrissi, Y., Cappellen, D., Durães, C., Boaventura, P., Vinagre, J., Azzi-Martin, L., Poglio, S., Cabeçadas, J., Campos, M. A., Beylot-Barry, M., Sobrinho-Simões, M., Merlio, J.-P., Soares, P., & Chevret, E. (2023). Spotlight on hTERT Complex Regulation in Cutaneous T-Cell Lymphomas. Genes, 14(2), 439. https://doi.org/10.3390/genes14020439