Targeted zinc-finger repressors to the oncogenic HBZ gene inhibit adult T-cell leukemia (ATL) proliferation
Scott, T.A. et al. (2023) Targeted zinc-finger repressors to the oncogenic HBZ gene inhibit adult T-cell leukemia (ATL) proliferation. NAR Cancer 5(1), 1–13. DOI: 10.1093/narcan/zcac046
Human T-lymphotropic virus type I (HTLV-I) is a retrovirus that infects CD4+ T cells and is transmitted by bodily fluids. Although infection may not result in symptoms in many cases, integration of viral RNA with the T-cell genome can later lead to adult T-cell leukemia/lymphoma (ATL). Progression of ATL results in a poor prognosis, and there is currently no effective treatment.
Recent studies have implicated the viral HTLV-I bZIP factor (HBZ) in oncogenesis. The current study examined a potential therapeutic strategy, using a series of zinc-finger protein (ZFP) repressors targeting a region of the HTLV-I promoter that controls HBZ expression. To select the lead candidate, the researchers screened a series of ZFP repressors, using cotransfection assays with a bi-directional expression vector. This vector contained the HTLV-LTR driving firefly and Renilla luciferase in the sense and antisense direction, respectively. Further experiments in patient-derived TL-Om1 cells identified a ZFP repressor that significantly inhibited cell proliferation, and the effect was specific to HTLV-I. In addition, the ZFP repressors induced cell cycle arrest and apoptosis in TL-Om1 cells. The researchers conclude that ZFP repressors specifically targeting HBZ gene expression could constitute an effective therapeutic approach against HTLV-I-associated malignancies.
Keywords: zinc-finger protein, HTLV-I, adult T-cell leukemia/lymphoma, ATL
