Therapy-induced selective loss of leukemia-initiating activity in murine adult T cell leukemia.

Abstract

Chronic HTLV-I (human T cell lymphotropic virus type I) infection may cause adult T cell leukemia/lymphoma (ATL), a disease with dismal long-term prognosis. The HTLV-I transactivator, Tax, initiates ATL in transgenic mice. In this study, we demonstrate that an As(2)O(3) and IFN-α combination, known to trigger Tax proteolysis, cures Tax-driven ATL in mice. Unexpectedly, this combination therapy abrogated initial leukemia engraftment into secondary recipients, whereas the primary tumor bulk still grew in the primary hosts, only to ultimately abate later on. This loss of initial transplantability required proteasome function. A similar regimen recently yielded unprecedented disease control in human ATL. Our demonstration that this drug combination targeting Tax stability abrogates tumor cell immortality but not short-term growth may foretell a favorable long-term efficiency of this regimen in patients.

• Authors: Hiba El Hajj, Marwan El-Sabban, Hideki Hasegawa, Ghazi Zaatari, Julien Ablain, Shahrazad T Saab, Anne Janin, Rami Mahfouz, Rihab Nasr, Youmna Kfoury, Christophe Nicot, Olivier Hermine, William Hall, Hugues de Thé, Ali Bazarbachi
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 207 Issue 13 Pg. 2785-92 (Dec 20 2010) ISSN: 1540-9538 [Electronic] United States
• PMID: 21135137 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Arsenicals
• Gene Products, tax
• Interferon-alpha
• Oxides
• Arsenic Trioxide

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis (drug effects)
• Arsenic Trioxide
• Arsenicals (administration & dosage)
• Cell Cycle (drug effects)
• Gene Products, tax (genetics)
• Human T-lymphotropic virus 1 (drug effects, genetics)
• Humans
• In Situ Nick-End Labeling
• Interferon-alpha (administration & dosage)
• Leukemia-Lymphoma, Adult T-Cell (drug therapy, pathology, virology)
• Mice
• Mice, SCID
• Mice, Transgenic
• Organ Size (drug effects)
• Oxides (administration & dosage)
• Reverse Transcriptase Polymerase Chain Reaction
• Spleen (drug effects, metabolism, pathology)
• Treatment Outcome