Thymus-derived leukemia-lymphoma in mice transgenic for the Tax gene of human T-lymphotropic virus type I.
Adult T-cell leukemia-lymphoma (ATLL) is a group of T-cell malignancies caused by infection with human T-lymphotropic virus type I (HTLV-I). Although the pathogenesis of ATLL remains incompletely understood, the viral regulatory protein Tax is centrally involved in cellular transformation. Here we describe the generation of HTLV-I Tax transgenic mice using the Lck proximal promoter to restrict transgene expression to developing thymocytes. After prolonged latency periods, transgenic mice developed diffuse large-cell lymphomas and leukemia with clinical, pathological and immunological features characteristic of acute ATLL. Transgenic mice were functionally immunocompromised and they developed opportunistic infections. Fulminant disease also developed rapidly in SCID mice after engraftment of lymphomatous cells from transgenic mice. Flow cytometry showed that the cells were CD4(-) and CD8(-), but CD44(+), CD25(+) and cytoplasmic CD3(+). This phenotype is indicative of a thymus-derived pre-T-cell phenotype, and disease development was associated with the constitutive activation of NF-kappaB. Our model accurately reproduces human disease and will provide a tool for analysis of the molecular events in transformation and for the development of new therapeutics.
Hasegawa
Hideki
H
Department of Pathology, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama-shi, Tokyo 208-0011, Japan.
Sawa
Hirofumi
H
Lewis
Martha J
MJ
Orba
Yasuko
Y
Sheehy
Noreen
N
Yamamoto
Yoshie
Y
Ichinohe
Takeshi
T
Tsunetsugu-Yokota
Yasuko
Y
Katano
Harutaka
H
Takahashi
Hidehiro
H
Matsuda
Junichiro
J
Sata
Tetsutaro
T
Kurata
Takeshi
T
Nagashima
Kazuo
K
Hall
William W
WW
D000818:Animals; D015415:Biomarkers; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D002874:Chromosome Mapping; D002875:Chromosomes; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D016355:Genes, pX; D015368:Human T-lymphotropic virus 1 / Q000235:genetics* / Q000648:ultrastructure; D006801:Humans; D007150:Immunohistochemistry; D007945:Leukemia, Lymphoid / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013953:Thymus Neoplasms / Q000276:immunology / Q000473:pathology*; D019076:Transgenes; D014184:Transplantation, Homologous
D015415:Biomarkers; D017252:CD3 Complex