Volume 12 Supplement 1

17th International Conference on Human Retroviruses: HTLV and Related Viruses

Open Access

Tax as a therapeutic target in ATL

  • Zeina Dassouki1, 2,
  • Umut Sahin2, 3, 4,
  • Hiba El Hajj1,
  • Florence Jollivet2, 3, 4,
  • Youmna Kfoury1,
  • Valérie Lallemand-Breitenbach2, 3, 4,
  • Olivier Hermine7,
  • Hugues de The2, 3, 4, 5, 6 and
  • Ali Bazarbachi1
Retrovirology201512(Suppl 1):P57

https://doi.org/10.1186/1742-4690-12-S1-P57

Published: 28 August 2015

The HTLV-1 Tax transactivator initiates transformation in adult T-cell leukemia/lymphoma (ATL), a highly aggressive chemotherapy-resistant malignancy. The arsenic/interferon combination, which triggers degradation of the Tax oncoprotein, selectively induces apoptosis of ATL cell lines and has significant clinical activity in Tax-driven murine ATL or patients. Yet, the role of Tax expression in maintaining the transformed phenotype and of Tax loss in ATL response is disputed and the molecular mechanisms driving degradation remain elusive. Here we demonstrate that ATL-derived or HTLV-1 transformed cells are addicted to continuous Tax expression, suggesting that Tax degradation underlies clinical responses to the arsenic/interferon combination. The latter enforces PML nuclear body (NB) formation and partner protein recruitment. In arsenic/interferon-treated ATL-derived cells, Tax is recruited onto NBs, undergoes PML-dependent hyper-sumoylation by SUMO2/3, but not SUMO1, ubiquitination by RNF4 and proteasome-dependent degradation. Thus, the arsenic/interferon combination clears ATL through degradation of its Tax driver and could have broader therapeutic value by promoting degradation of other pathogenic sumoylated proteins.

Authors’ Affiliations

(1)
Department of Internal Medicine, Faculty of Medicine, American University of Beirut
(2)
Université Paris Diderot, Sorbonne Paris Cité
(3)
INSERM UMR 944, Equipe labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie
(4)
CNRS UMR 7212
(5)
AP-HP, Service de Biochimie
(6)
College de France
(7)
CNRS UMR 8147, Hôpital Necker

Copyright

© Dassouki et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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