Dual cytoplasmic and nuclear localization of HTLV-1-encoded HBZ protein is a unique feature of adult T cell leukemia

Haematologica. 2021 Feb 25. doi: 10.3324/haematol.2020.272468. Online ahead of print.

Abstract

Adult T-cell leukemia-lymphoma (ATL), is a highly malignant T-cell neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1), characterized by a poor prognosis. Two viral proteins, Tax-1 and HBZ play important roles in the pathogenesis of ATL. While Tax-1 can be found in both cytoplasm and nucleus of HTLV-1 infected patients, HBZ is exclusively localized in the cytoplasm of HTLV-1 asymptomatic carriers and patients with chronic neurologic disease HAM/TSP, and only in the nucleus of ATL cell lines, suggesting that the nuclear localization of HBZ can be a hallmark of neoplastic transformation. To clarify this crucial point, here we investigated in detail the pattern of HBZ expression in ATL patients. We made use of our monoclonal antibody 4D4-F3, that at present is a uniquely reported reagent, among the few described, able to detect endogenous HBZ by immunofluorescence and confocal microscopy in cells from asymptomatic carriers, HAM/TSP and ATL patients. We found that HBZ localizes both in the cytoplasm and in the nucleus of cells of ATL patients irrespective of their clinical status, with a strong preference for the cytoplasmic localization. Also Tax-1 localized in both compartments. As HBZ is exclusively localized in the cytoplasm in asymptomatic carriers and in non-neoplastic pathologies, this finding shows that neoplastic transformation consequent to HTLV-1 infection is accompanied and associated with the capacity of HBZ to translocate to the nucleus, which suggests a role of cytoplasmic-to-nuclear translocation in HTLV-1-mediated oncogenesis.