High TERF2 expression is associated with poor prognosis and its suppression attenuates progression in acute myeloid leukemia.

[BACKGROUND] Telomeric repeat-binding factor 2 (TERF2/TRF2), a core constituent of the shelterin complex that orchestrates telomere protection mechanisms, plays a pivotal role in preserving telomere structural integrity and maintaining genomic homeostasis. While dysregulated TERF2 expression has been implicated in tumorigenesis, its functional role and clinical relevance in acute myeloid leukemia (AML) remain poorly defined. Therefore, this study aimed to elucidate the functional role, underlying mechanisms, and clinical relevance of TERF2 in AML.

[METHODS] TERF2 messenger RNA (mRNA) expression in peripheral blood mononuclear cells (PBMCs) from AML patients was quantified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Transcriptomic data from The Cancer Genome Atlas (TCGA) database and Genotype-Tissue Expression (GTEx) databases were analyzed to assess TERF2's prognostic significance. The viability of AML cells was assessed using Cell Counting Kit-8 (CCK-8) assay, while cell cycle and apoptosis were analyzed via flow cytometry with propidium iodide (PI) staining and fluorescein isothiocyanate-labelled annexin V (annexin V-FITC) dual-labeling, respectively. An orthotopic xenograft model in NOD-SCID IL2rg (NSG) mice was established to monitor leukemia burden via bioluminescence imaging.

[RESULTS] TERF2 was significantly overexpressed in AML patients and correlated with adverse clinicopathological features, including elevated white blood cell counts (WBCs), increased bone marrow (BM) blast percentages, and higher peripheral blood (PB) blast counts. Clinically, high TERF2 expression predicted shorter overall survival (OS). TERF2 knockdown induced apoptosis, suppressed cell proliferation, and downregulated the E2F pathway, while simultaneously enhancing cuproptosis susceptibility, as evidenced by reduced half-maximal inhibitory concentration (IC) values of the elesclomol-copper (ES-Cu). , TERF2 silencing attenuated AML progression and synergized with elesclomol to prolong survival.

[CONCLUSIONS] TERF2 is overexpressed in AML, with a marked correlation between TERF2 levels and clinicopathological features, suggesting a potential role for TERF2 in the prognosis of AML. Downregulation of TERF2 inhibits the AML cell proliferation, induces apoptosis, and modulates cuproptosis sensitivity possibly via the E2F-mediated pathway. Targeting TERF2 not only inhibits proliferation but also unlocks cuproptosis as a therapeutic vulnerability, offering a potential strategy for AML.