Targeted zinc-finger repressors to the oncogenic HBZ gene inhibit adult T-cell leukemia (ATL) proliferation.
Tristan A ScottCitradewi SoemardyRoslyn M RayKevin V MorrisPublished in: NAR cancer (2023)
Human T-lymphotropic virus type I (HTLV-I) infects CD4+ T-cells resulting in a latent, life-long infection in patients. Crosstalk between oncogenic viral factors results in the transformation of the host cell into an aggressive cancer, adult T-cell leukemia/lymphoma (ATL). ATL has a poor prognosis with no currently available effective treatments, urging the development of novel therapeutic strategies. Recent evidence exploring those mechanisms contributing to ATL highlights the viral anti-sense gene HTLV-I bZIP factor (HBZ) as a tumor driver and a potential therapeutic target. In this work, a series of zinc-finger protein (ZFP) repressors were designed to target within the HTLV-I promoter that drives HBZ expression at highly conserved sites covering a wide range of HTLV-I genotypes. ZFPs were identified that potently suppressed HBZ expression and resulted in a significant reduction in the proliferation and viability of a patient-derived ATL cell line with the induction of cell cycle arrest and apoptosis. These data encourage the development of this novel ZFP strategy as a targeted modality to inhibit the molecular driver of ATL, a possible next-generation therapeutic for aggressive HTLV-I associated malignancies.
Keyphrases
- poor prognosis
- cell cycle arrest
- transcription factor
- long non coding rna
- cell death
- pi k akt
- sars cov
- signaling pathway
- end stage renal disease
- bone marrow
- acute myeloid leukemia
- genome wide identification
- genome wide
- endothelial cells
- dna methylation
- cancer therapy
- chronic kidney disease
- copy number
- oxidative stress
- childhood cancer
- binding protein
- prognostic factors
- single cell
- papillary thyroid
- gene expression
- cell therapy
- drug delivery
- young adults
- endoplasmic reticulum stress
- lymph node metastasis
- squamous cell
- amino acid
- protein protein
- artificial intelligence
- climate change
- induced pluripotent stem cells