Therapy-induced selective loss of leukemia-initiating activity in murine adult T cell leukemia.
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.
Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon.
Hiba
H
El Hajj
Marwan
M
El-Sabban
Hideki
H
Hasegawa
Ghazi
G
Zaatari
Julien
J
Ablain
Shahrazad T
ST
Saab
Anne
A
Janin
Rami
R
Mahfouz
Rihab
R
Nasr
Youmna
Y
Kfoury
Christophe
C
Nicot
Olivier
O
Hermine
William
W
Hall
Hugues
H
de Thé
Ali
A
Bazarbachi
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage; D002453:Cell Cycle / Q000187:drug effects; D016356:Gene Products, tax / Q000235:genetics; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D020287:In Situ Nick-End Labeling; D016898:Interferon-alpha / Q000008:administration & dosage; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D009929:Organ Size / Q000187:drug effects; D010087:Oxides / Q000008:administration & dosage; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
D001152:Arsenicals; D016356:Gene Products, tax; D016898:Interferon-alpha; D010087:Oxides; D000077237:Arsenic Trioxide