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G. Forlani et al.
clear that a quota of the HBZ molecular pool can translo- cate into the nucleus and can be retained there to func- tionally participate in the maintenance of the leukemic phenotype. The molecular basis of this nuclear retention remains to be investigated.
An additional relevant aspect of the present study was the expression and subcellular localization of Tax-1 pro- tein. Tax-1 was not expressed in three of eight patients analyzed in this study, confirming previous findings on the silencing of the viral oncogene in ATL.19 Interestingly, however, a clear difference was observed between acute and chronic ATL, as Tax-1 was expressed in three of four acute ATL in a relevant proportion of cells, ranging from 8.4% to 65.0% of PBMC, and only in two of four chronic ATL but in a considerably low proportion of cells, namely 1.0% and 6.4 % of PBMC. This finding correlated quite well with the cell surface phenotype of leukemic cells in that PBMC of chronic ATL patients resembled more close- ly the phenotype observed in healthy individuals.
An exclusive Tax-1 nuclear localization was found in very few cases and only in acute ATL, whereas the vast majority of the Tax-1-positive cells expressed the viral protein both in the cytoplasm and nucleus. The fact that in acute ATL cases analyzed in this study Tax-1 was expressed in a considerable proportion of cells, although unexpected, may indeed support the idea that increased and/or sustained cell proliferation observed in the acute leukemic state is associated with a burst of Tax-1 expres- sion, as recently proposed.49,50 Furthermore, both in acute and in chronic ATL most of Tax-1-positive cells were also HBZ-positive suggesting a distinct behaviour with respect to what has been recently found in asymptomatic
carriers and HAM/TSP patients in which HBZ and Tax-1 were very rarely found co-expressed in the same cells.26,27 As stressed above, this may be correlated with the dis- tinct replicative state of the cells in asymptomatic carriers and HAM/TSP patients as compared to leukemic patients.
In conclusion, the results presented in this study estab- lish for the first time a correlation between modification of the subcellular localization of HBZ and acquisition of neoplastic state in subjects infected by HTLV-1. Future studies will be devoted to the clarification of the intimate molecular mechanisms that are at the basis of the cyto- plasmic and nuclear retention of HBZ in HTLV-1-mediated leukemogenesis.
Disclosures
No conlicts of interest to disclose.
Contributions
GF and RSA conceived the experiments, performed data analysis, wrote and revised the manuscript; GF, MS, AT and IC performed the experiments; AM and OH provided ATL samples and reviewed the manuscript.
Funding
This study was supported by the University of Insubria “FAR 2018 and 2019” (to RSA and GF); by The Institutional Grant 2017, University of Insubria (to RSA); in part by the European Community FP7 Grant no. 602893 “Cancer Vaccine Development for Hepatocellular Carcinoma-HepaVAC” http://www.hepavac.eu (to RSA, and GF); by grants from the Institut National du Cancer (INCA), France (to OH and FM).
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