Loading…

ATL response to arsenic/interferon therapy is triggered by SUMO/PML/RNF4-dependent Tax degradation

The human T-cell lymphotropic virus type I (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 a...

Full description

Saved in:
Bibliographic Details
Published in:Blood 2015-01, Vol.125 (3), p.474-482
Main Authors: Dassouki, Zeina, Sahin, Umut, El Hajj, Hiba, Jollivet, Florence, Kfoury, Youmna, Lallemand-Breitenbach, Valérie, Hermine, Olivier, de Thé, Hugues, Bazarbachi, Ali
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The human T-cell lymphotropic virus type I (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 human patients. However, the role 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 dependent on continuous Tax expression, suggesting that Tax degradation underlies clinical responses to the arsenic/interferon combination. The latter enforces promyelocytic leukemia protein (PML) nuclear body (NB) formation and partner protein recruitment. In arsenic/interferon-treated HTLV-1 transformed or ATL cells, Tax is recruited onto NBs and undergoes PML-dependent hyper-sumoylation by small ubiquitin-like modifier (SUMO)2/3 but not SUMO1, ubiquitination by RNF4, and proteasome-dependent degradation. Thus, the arsenic/interferon combination clears ATL through degradation of its Tax driver, and this regimen could have broader therapeutic value by promoting degradation of other pathogenic sumoylated proteins. •Survival of ATL cells depends on continuous Tax expression.•Arsenic/interferon combination induces SUMO/PML/RNF4-mediated Tax degradation.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2014-04-572750