Thymus-derived leukemia-lymphoma in mice transgenic for the Tax gene of human T-lymphotropic virus type I

Abstract

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.

Human T cell leukemia virus type 1 (HTLV-1) and oncogene or oncomiR addiction?

“…Extant findings have shown that Tax is sufficient to transform human T cells [10,11]. Hence, the expression of Tax-alone in transgenic mice was found to be fully proficient for in vivo tumorigenesis [12][13][14]. Indeed, current data are consistent with the notion that Tax expression in infected humans greatly accelerates the in vivo cycling of T cells [15].…”

TCF1 and LEF1 act as T-cell intrinsic HTLV-1 antagonists by targeting Tax

“…However, transgenic expression of Tax in the thymus induced immature T-cell lymphomas (36). These findings suggest that overexpression of Tax is oncogenic even for thymocytes, but that Tax expression or functions are normally impaired in the thymus of infected individuals.…”

Human T-Cell Leukemia Virus Type 1 Tax Protein Down-Regulates Pre-T-Cell Receptor Alpha Gene Transcription in Human Immature Thymocytes

“…In addition, as exemplified with the E2A-deficient mice, the expression of Tax, by inactivating E2A proteins in immature thymocytes, might be followed by the emergence of a malignant lymphoproliferation. Thus, transgenic mice, in which Tax is expressed under the control of the Lck proximal promoter (which restricts transgene expression to developing thymocytes), after a long latency period develop lymphoma and leukemia with constitutive activation of NF-B (20). As a matter of fact, activation of this pathway is one of the main features of ATL cells, in which Tax expression is not or is rarely detected (14,17).…”