Functional and phenotypic studies of Japanese adult T cell leukemia cells.

Morimoto, Chikao; Matsuyama, Tomohiko; Oshige, C; Tanaka, Hiroko; Hercend, T; Reinherz, Ellis L.; Schlossman, S F

doi:10.1172/jci111780

Cited by 56 publications

(14 citation statements)

References 51 publications

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“…We and others have demonstrated that HTLV-1 and HTLV-2 can infect and transform both CD4 ϩ and CD8 ϩ T-cell subtypes in culture, but HTLV-1 preferentially transforms CD4 ϩ T-cells, whereas HTLV-2 favors CD8 ϩ T-cell transformation (28,33,37,44,46). Moreover, this in vitro transformation tropism is consistent with several reports on HTLV-1 and HTLV-2 in vivo tropism and disease association (20,21,29,36). One in vitro study has indicated that Tax-mediated transcription of HTLV-1 is significantly increased in purified CD4…”

Section: Discussionsupporting

confidence: 89%

Tax and Overlapping Rex Sequences Do Not Confer the Distinct Transformation Tropisms of Human T-Cell Leukemia Virus Types 1 and 2

Xie²,

Green

2003

J Virol

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Human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 are distinct oncogenic retroviruses that infect several cell types but display their biological and pathogenic activity only in T cells. Previous studies have indicated that in vivo HTLV-1 has a preferential tropism for CD4 ؉ T cells, whereas HTLV-2 in vivo tropism is less clear but appears to favor CD8 ؉ T cells. Both CD4 ؉ and CD8 ؉ T cells are susceptible to HTLV-1 and HTLV-2 infection in vitro, and HTLV-1 has a preferential immortalization and transformation tropism of CD4 ؉ T cells, whereas HTLV-2 immortalizes and transforms primarily CD8 ؉ T cells. The molecular mechanism that determines this tropism of HTLV-1 and HTLV-2 has not been determined. HTLV-1 and HTLV-2 carry the tax and rex transregulatory genes in separate but partially overlapping reading frames. Since Tax has been shown to be critical for cellular transformation in vitro and interacts with numerous cellular processes, we hypothesized that the viral determinant of transformation tropism is encoded by tax. Using molecular clones of HTLV-1 (Ach) and HTLV-2 (pH6neo), we constructed recombinants in which tax and overlapping rex genes of the two viruses were exchanged. p19 Gag expression from proviral clones transfected into 293T cells indicated that both recombinants contained functional Tax and Rex but with significantly altered activity compared to the wild-type clones. Stable transfectants expressing recombinant viruses were established, irradiated, and cocultured with peripheral blood mononuclear cells. Both recombinants were competent to transform T lymphocytes with an efficiency similar to that of the parental viruses. Flow cytometry analysis indicated that HTLV-1 and HTLV-1/TR2 had a preferential tropism for CD4؉ T cells and that HTLV-2 and HTLV-2/TR1 had a preferential tropism for CD8 ؉ T cells. Our results indicate that tax/rex in different genetic backgrounds display altered functional activity but ultimately do not contribute to the different in vitro transformation tropisms. This first study with recombinants between HTLV-1 and HTLV-2 is the initial step in elucidating the different pathobiologies of HTLV-1 and HTLV-2.

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Section: Discussionsupporting

confidence: 89%

Tax and Overlapping Rex Sequences Do Not Confer the Distinct Transformation Tropisms of Human T-Cell Leukemia Virus Types 1 and 2

Xie²,

Green

2003

J Virol

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“…It has been shown that fresh ATLL cells are present in the absence of the TCR/CD3 and CD7 molecules on their surface. 6,7 A correlation between the level of CD3 genes transcription and the CD7 surface expression in adult human marrow T-cell progenitors has also been demonstrated. 8 Furthermore, immunohistochemical studies in ATLL showed that the lack of CD7 expression was a typical characteristic of the malignant lymphocytes.…”

Section: Introductionmentioning

confidence: 89%

HTLV-I infection of WE17/10 CD4+ cell line leads to progressive alteration of Ca2+ influx that eventually results in loss of CD7 expression and activation of an antiapoptotic pathway involving AKT and BAD which paves the way for malignant transformation

Akl

Badran

Zein³

et al. 2007

Leukemia

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Adult T-cell leukemia/lymphoma (ATLL) is a malignancy slowly emerging from human T-cell leukemia virus type 1 (HTLV-I)-infected mature CD4 þ T-cells. To characterize the molecular modifications induced by HTLV-I infection, we compared HTLV-I-infected WE17/10 cells with control cells, using micro-arrays. Many calcium-related genes were progressively downmodulated over a period of 2 years. Infected cells acquired a profound decrease of intracellular calcium levels in response to ionomycin, timely correlated with decreased CD7 expression. Focusing on apoptosis-related genes and their relationship with CD7, we observed an underexpression of most antiapoptotic genes. Western blotting revealed increasing Akt and Bad phosphorylation, timely correlated with CD7 loss. This was shown to be phosphatidylinositol 3-kinase (PI3K)-dependent. Activation of PI3K/Akt induced resistance to the apoptotic effect of interleukin-2 deprivation. We thus propose the following model: HTLV-I infection induces a progressive decrease in CD3 genes expression, which eventually abrogates CD3 expression; loss of CD3 is known to perturb calcium transport. This perturbation correlates with loss of CD7 expression and induction of Akt and Bad phosphorylation via activation of PI3K. The activation of the Akt/Bad pathway generates a progressive resistance to apoptosis, at a time HTLV-I genes expression is silenced, thus avoiding immune surveillance. This could be a major event in the process of the malignant transformation into ATLL.

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“…In the case of 8.7 and 8.8, this loss occurred despite repeated antigenic stimulation, suggesting that a lack of antigenic exposure was not the cause of the loss of function. 1470 Yarchoan, Guo, Reitz, Jr., Maluish, Mitsuya, and Broder (28)(29)(30)(31). It has been hypothesized that this suppression may be a result ofthe high level of IL-2 R expression absorbing IL-2 from the culture medium; the failure to observe suppression by 8.8H3 argues against this mechanism.…”

Section: Discussionmentioning

confidence: 99%

Alterations in cytotoxic and helper T cell function after infection of T cell clones with human T cell leukemia virus, type I.

et al. 1986

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Functional and phenotypic studies of Japanese adult T cell leukemia cells.

Cited by 56 publications

References 51 publications

Tax and Overlapping Rex Sequences Do Not Confer the Distinct Transformation Tropisms of Human T-Cell Leukemia Virus Types 1 and 2

Tax and Overlapping Rex Sequences Do Not Confer the Distinct Transformation Tropisms of Human T-Cell Leukemia Virus Types 1 and 2

HTLV-I infection of WE17/10 CD4+ cell line leads to progressive alteration of Ca2+ influx that eventually results in loss of CD7 expression and activation of an antiapoptotic pathway involving AKT and BAD which paves the way for malignant transformation

Alterations in cytotoxic and helper T cell function after infection of T cell clones with human T cell leukemia virus, type I.

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