Tax of the Human T-Lymphotropic Virus Type I Transactivates Promoter of theMDR-1Gene

Chuang, Shuang‐En; Doong, Shin-Lian; Lin, Ming Tseh; Cheng, Ann‐Lii

doi:10.1006/bbrc.1997.7326

Cited by 7 publications

(2 citation statements)

References 29 publications

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“…It has been reported that Tax can transactivate the MDR-1 (multidrug resistance) gene promoter [25] and that ATLL cells very often show an enhanced MDR-1 expression [26]. Hence, we tested whether the observed increased resistance of JD1 cells could be ascribable to P-glycoprotein overexpression.…”

Section: Resultsmentioning

confidence: 99%

Ras signaling contributes to survival of human T-cell leukemia/lymphoma virus type 1 (HTLV-1) Tax-positive T-cells

2011

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Ras signaling pathways play an important role in cellular proliferation and survival, and inappropriate activation of Ras frequently results in cell transformation and cancer. Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) is the etiological agent of the adult T-cell leukemia/lymphoma (ATLL), a severe malignancy that has a poor prognosis and exhibits resistance to conventional chemotherapy. Although the mechanisms involved in cell transformation by HTLV-1 have not been completely clarified, it is generally thought that Tax plays a pivotal role in the process. We have previously proposed that a functionally active Ras protein is needed for efficient anti-apoptotic activity of Tax. In this study we report data indicating that the apoptotic resistance of cells expressing Tax, constitutively or transiently, is linked to the intracellular levels of Ras-GTP. Indeed, we found that Tax-positive cells have a high content of active Ras, and that inhibition of Ras signaling, using the antagonist farnesyl thyosalicylic acid (FTS), increases their sensitivity to apoptosis. FTS treatment was also accompanied by a decrease in ERK, but not Akt, phosphorylation. Thus, all together our data suggest that the interaction between Tax and Ras could be important to ATLL pathogenesis, and indicate Ras as a possible target for therapeutic intervention in ATLL patients.

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Section: Resultsmentioning

confidence: 99%

Ras signaling contributes to survival of human T-cell leukemia/lymphoma virus type 1 (HTLV-1) Tax-positive T-cells

2011

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“…Together, these results reinforce the idea that there are multiple premalignant clones in the tumoural tissue from patients with ATLL (Tsukasaki et al, 1997;Cavrois et al, 1996) and suggest that some clones harbour distinct sensitivities to treatment. Tax transactivates the promoter of the multidrug resistance gene (MDR-1, Chuang et al, 1997) which confers resistance to chemotherapy. It has been shown that naturally occurring variants of Tax protein can modify its transactivation function (Niewiesk et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Semiquantitative analysis of residual disease in patients treated for adult T‐cell leukaemia/lymphoma (ATLL)

et al. 1999

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Summary. Many adult T-cell leukaemia/lymphoma (ATLL)patients who respond to induction treatment, then relapse. Knowing the clonality pattern of residual tumourous clones during treatment could help understand disease evolution and aid therapeutic decisions. We developed a sensitive and semi-quantitative molecular analysis of these clones in ATLL patients. DNA samples from PBMCs derived from eight ATLL patients were studied over time by quadruplicate linker mediated PCR (LMPCR) amplification of HTLV-1 integration sites. Patients were treated with combination chemotherapy, zidovudine-interferon-alpha and/or by peripheral stem cell transplantation or allogeneic bone marrow transplantation. Persistence of tumourous clones at a high frequency (>1/ 300 PBMCs) was frequently observed, even in complete responders, and was invariably correlated with relapse and/ or poor outcome. Fluctuation in the frequency of some tumourous clones was observed with evidence for clonal change under treatment in one patient, indicating that treatment of ATLL can result in the selection of resistant clones. Finally, allogeneic bone marrow transplantation (BMT) using an HTLV-1 infected sibling as donor was found to be associated with long-lasting disappearance of tumourous clones and a possible cure of the disease. Longterm persistent clonal expansion of circulating HTLV-1 bearing T cells which derived from the donor bone marrow was evidenced in this patient. In conclusion, variable success in treatment of ATLL is probably due to the clonal heterogeneity which results in the selection of resistant clones. Semi-quantitative assessment of residual disease (RD) through LMPCR may predict treatment failure. Accordingly, additional therapy may be tailored to the clonality pattern observed after first-line therapy.

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The Mechanism of Trans-activation of theMDR1Gene by Human T-Cell Leukemia Virus

Lau

Gant

Cann

1998

Biochemical and Biophysical Research Communications

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Tax of the Human T-Lymphotropic Virus Type I Transactivates Promoter of theMDR-1Gene

Cited by 7 publications

References 29 publications

Ras signaling contributes to survival of human T-cell leukemia/lymphoma virus type 1 (HTLV-1) Tax-positive T-cells

Ras signaling contributes to survival of human T-cell leukemia/lymphoma virus type 1 (HTLV-1) Tax-positive T-cells

Semiquantitative analysis of residual disease in patients treated for adult T‐cell leukaemia/lymphoma (ATLL)

The Mechanism of Trans-activation of theMDR1Gene by Human T-Cell Leukemia Virus

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