Beyond Telomeres: Unveiling the Extratelomeric Functions of TERT in B-Cell Malignancies
Simple Summary
Abstract
1. Introduction
2. Telomere Erosion—A Driving Force in Oncogenesis
3. Telomerase
Regulation of TERT Expression and Telomerase Activity
4. Telomeres and Telomerase in Normal and Neoplastic B Cells
5. TERT’s Non-Canonical Functions: Focus on B-Cell Malignancies
6. Telomerase Inhibition Strategies
Importance of TERT Inhibition in B-Cell Malignancies
7. Conclusions and Future Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
TERT | telomerase reverse transcriptase |
TERC | telomerase RNA component |
DDR | DNA damage response |
ATM | ATM serine/threonine kinase |
ATR | ATR serine/threonine kinase |
TP53 | tumor protein p53 |
RB1 | RB transcriptional corepressor 1 |
p16 | cyclin-dependent kinase inhibitor 2A |
ALT | Alternative Lengthening of Telomeres |
SP1 | Sp1 transcription factor |
MYC | MYC proto-oncogene, bHLH transcription factor |
HIF1A | hypoxia-inducible factor 1 subunit alpha |
AP-2 | transcription factor AP-2 alpha |
ETS | E-twenty-six |
TCF | ternary complex factors |
NF-κB | RELA proto-oncogene |
β-catenin | catenin beta 1 |
WT1 | Wilms’ Tumor 1 |
NFX-1 | Nuclear Transcription Factor X-Box Binding |
MAD1 | MAX dimerization protein 1 |
CTCF | CCCTC Binding Factor |
PI3K | phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha |
AKT1 | serine/threonine kinase 1 |
HBV | hepatitis B virus |
HCV | hepatitis C virus |
KSHV | Kaposi’s sarcoma-associated herpes virus |
EBV | Epstein–Barr virus |
CMV | cytomegalovirus |
HTLV-1 | human T-cell leukemia virus-1 |
LCL | lymphoblastoid cell line |
LMP1 | latent membrane protein 1 |
MAPK | mitogen-activated protein kinase 1 |
ERK1/2 | extracellular signal-regulated kinase 1/2 |
GC | germinal center |
DLBCL | diffuse large B-cell lymphoma |
BL | Burkitt lymphoma |
CLL | chronic lymphocytic leukemia |
WNT | wingless-type MMTV integration site family |
BCL2 | BCL2 apoptosis regulator |
P21 | cyclin-dependent kinase inhibitor 1A |
FOXO3 | forkhead box O3 |
NOXA | phorbol-12-myristate-13-acetate-induced protein 1 |
BAD | BCL2-associated agonist of cell death |
NOTCH2 | notch receptor 2 |
BATF | basic leucine zipper ATF-like transcription factor |
BZLF1 | BamHI Z fragment leftward open reading frame 1 |
ZIF-8 | zeolitic imidazole framework-8 |
ROS | reactive oxygen species |
BRG1 | SWI/SNF-related BAF chromatin remodeling complex subunit ATPase 4 |
IL6 | interleukin 6 |
TNFα | tumor necrosis factor |
NME2 | NME/NM23 nucleoside diphosphate kinase 2 |
TOM 20 | translocase of outer mitochondrial membrane 20 |
TOM 40 | translocase of outer mitochondrial membrane 40 |
TIM 23 | translocase of inner mitochondrial membrane 23 |
COX | cyclooxygenase-1 |
ACSL4 | acyl-CoA synthetase long-chain family member 4 |
SLC7A11 | solute carrier family 7 member 11 |
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B-Malignancy | TERT’s Extratelomeric Function(s) | Reference |
---|---|---|
EBV-immortalized lymphoblastoma cell lines | Increased TERT levels promote EBV latency program, increase resistance to lytic cycle induction, and enhance in vitro growth properties. | [68] |
EBV-immortalized lymphoblastoma cell lines; EBV-negative and -positive BL cell lines | TERT inhibition via shTERT RNA, decreasing BATF and increasing BZLF1 expression, induces the EBV lytic cycle. In both EBV-positive and -negative cells, TERT inhibition reduces proliferation and triggers AKT1/FOXO3/NOXA-dependent apoptosis. | [89] |
EBV-immortalized lymphoblastoma cell lines | High TERT levels activate NOTCH2 through the NF-κB signaling pathway. In turn, NOTCH2 induces BATF, which suppresses BZLF1 viral expression, thereby promoting EBV latency. | [90] |
EBV-immortalized lymphoblastoma cell lines; EBV-positive and -negative BL cell lines | Short-term inhibition of TERT by BIBR1532 causes cell cycle arrest and apoptosis, associated with activation of DDR independently of telomere shortening. TERT inhibition sensitizes cells to the pro-apoptotic effects of chemotherapeutic agents. | [91] |
EBV-immortalized lymphoblastoma cell lines; EBV-negative BL cell lines | Short-term TERT inhibition by BIBR1532 reduces proliferation and impairs the viability of LCL and BL cells xenografted in zebrafish through cell cycle arrest and apoptosis driven by DDR activation, independently of telomere shortening. | [92] |
EBV-immortalized lymphoblastoma cell lines; EBV-negative BL cell lines | Short-term inhibition of TERT by BIBR1532 impairs cell growth by downregulating MYC via NF-κB signaling. Combined treatment with TERT inhibitor and chemotherapeutic agents induces a cumulative inhibitory effect on the proliferation of LCL and BL cells xenografted in zebrafish. | [78] |
EBV-positive B-cell lymphoma cell line | Triptolide inhibits TERT expression and activity by downregulating SP1 and MYC. Triptolide promotes the lytic cycle of EBV. | [93] |
Lymphoblastoma cell line and primary leukemic cells from B-ALL | Short-term inhibition of TERT by shTERT RNA decreases MYC protein stability, leading to the reduced transcription of its target genes and impairing cell viability without affecting the telomere length. | [77] |
Primary leukemic cells from ALL | Telomerase inhibition with MST-312 for 48 hours significantly reduces levels of IL6 in primary leukemic cells by inhibiting NF-κB signaling. | [76] |
Pre-B ALL cell line | Treatment with BIBR1532 for 48 h impairs cell proliferation and causes cell death, likely by reducing Survivin-mediated MYC and TERT levels. | [94] |
Pre-B ALL cell line | Treatment with BIBR1532 for 24 h enhances ROS production and increases the anti-proliferative and pro-apoptotic effects of doxorubicin by upregulating TP73 and p21 and downregulating MYC and TERT. | [95] |
Pre-B ALL cell lines | The telomerase inhibitor MST-312 shows dose-dependent cytotoxic and apoptotic effects on pre-B ALL cells. A 48 h combination with doxorubicin enhances cytotoxicity and apoptosis, linked to reductions in BCL2, MYC, and TERT and an increase in BAX. | [96] |
Pre-B ALL cell line | A 48 h combined treatment with MST-312 and NU7441, a DNA-PK inhibitor, synergistically induces anti-proliferative and pro-apoptotic effects, downregulating MYC, TERT, and BCL2 and upregulating BAX. | [97] |
Pre-B ALL cell lines | Short-term TERT inhibition by siRNA reduces proliferation and viability, associated with the upregulation of BAX and downregulation of BCL2. The cytotoxicity of TERT inhibition is characterized by the upregulation of ferroptosis promoters (lipid-ROS, ACSL4) and suppression of inhibitors (SLC7A11). | [98] |
Human multiple myeloma cell line | Treatment with MST-312 for 48 h induces anti-proliferative and pro-apoptotic effects, by downregulating MYC, TERT, BCL2, IL6, and TNFα and upregulating BAX. | [99] |
Multiple myeloma cell lines | Treatment with BIBR1532 for 48 h inhibits cell proliferation and promotes apoptosis associated with the downregulation of TERT, MYC, BCL-XL, and Survivin; increased BAD levels; the dephosphorylation of PI3K, AKT1, and mTOR; and the increased phosphorylation of ERK1/2 and MAPK. BIBR1532, combined with doxorubicin or bortezomib, exhibits a synergistic pro-apoptotic effect. | [100] |
Multiple myeloma cancer stem cells from cell lines and primary clinical specimens | Short-term telomerase inhibition by Imetelstat reduces clonogenic growth and promotes differentiation by downregulating stemness-related genes, without affecting the telomere length. | [101] |
Philadelphia chromosome-positive B-lymphoblastic leukemia cell line | Short-term treatment with the telomerase inhibitor Imetelstat demonstrates dose-dependent suppression of cell proliferation, unrelated to telomere length: at higher concentrations, it induces increased levels of γH2AX. | [102] |
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Giunco, S.; Petrara, M.R.; Indraccolo, S.; Ciminale, V.; De Rossi, A. Beyond Telomeres: Unveiling the Extratelomeric Functions of TERT in B-Cell Malignancies. Cancers 2025, 17, 1165. https://doi.org/10.3390/cancers17071165
Giunco S, Petrara MR, Indraccolo S, Ciminale V, De Rossi A. Beyond Telomeres: Unveiling the Extratelomeric Functions of TERT in B-Cell Malignancies. Cancers. 2025; 17(7):1165. https://doi.org/10.3390/cancers17071165
Chicago/Turabian StyleGiunco, Silvia, Maria Raffaella Petrara, Stefano Indraccolo, Vincenzo Ciminale, and Anita De Rossi. 2025. "Beyond Telomeres: Unveiling the Extratelomeric Functions of TERT in B-Cell Malignancies" Cancers 17, no. 7: 1165. https://doi.org/10.3390/cancers17071165
APA StyleGiunco, S., Petrara, M. R., Indraccolo, S., Ciminale, V., & De Rossi, A. (2025). Beyond Telomeres: Unveiling the Extratelomeric Functions of TERT in B-Cell Malignancies. Cancers, 17(7), 1165. https://doi.org/10.3390/cancers17071165