Adhesion-dependent growth of primary adult T cell leukemia cells with down-regulation of HTLV-I p40Tax protein: a novel in vitro model of the growth of acute ATL cells

Nagai, Kazuhiro; Jinnai, Itsuro; Hata, Tomoko; Usui, Toshiaki; Sasaki, Daisuke; Tsukasaki, Kunihiro; Sugahara, Kazuyuki; Hishikawa, Yoshitaka; Yamada, Yasuaki; Tanaka, Yuetsu; Koji, Takehiko; Mano, Hiroyuki; Kamihira, Shimeru; Tomonaga, Masao

doi:10.1007/s12185-008-0207-z

Cited by 8 publications

(7 citation statements)

References 56 publications

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“…Several reports suggested importance of interaction with normal epithelial cells and mesenchymal stem cells. [121][122][123] Furthermore, involvement of angiogenesis and fibroblast-derived osteopontin has been suggested in proliferation and survival, as well as possible roles of exosomes produced by ATL cells. [124][125][126] In this regard, a possible role of mutations of Notch1 signaling 70,87 appears to deserve further examination.…”

Section: Summary and Perspectivesmentioning

confidence: 99%

Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1–infected T cells

Watanabe

2017

Blood

142

117

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Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) that develops through a multistep carcinogenesis process involving 5 or more genetic events. We provide a comprehensive overview of recently uncovered information on the molecular basis of leukemogenesis in ATL. Broadly, the landscape of genetic abnormalities in ATL that include alterations highly enriched in genes for T-cell receptor–NF-κB signaling such as PLCG1, PRKCB, and CARD11 and gain-of function mutations in CCR4 and CCR7. Conversely, the epigenetic landscape of ATL can be summarized as polycomb repressive complex 2 hyperactivation with genome-wide H3K27 me3 accumulation as the basis of the unique transcriptome of ATL cells. Expression of H3K27 methyltransferase enhancer of zeste 2 was shown to be induced by HTLV-1 Tax and NF-κB. Furthermore, provirus integration site analysis with high-throughput sequencing enabled the analysis of clonal composition and cell number of each clone in vivo, whereas multicolor flow cytometric analysis with CD7 and cell adhesion molecule 1 enabled the identification of HTLV-1–infected CD4+ T cells in vivo. Sorted immortalized but untransformed cells displayed epigenetic changes closely overlapping those observed in terminally transformed ATL cells, suggesting that epigenetic abnormalities are likely earlier events in leukemogenesis. These new findings broaden the scope of conceptualization of the molecular mechanisms of leukemogenesis, dissecting them into immortalization and clonal progression. These recent findings also open a new direction of drug development for ATL prevention and treatment because epigenetic marks can be reprogrammed. Mechanisms underlying initial immortalization and progressive accumulation of these abnormalities remain to be elucidated.

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Section: Summary and Perspectivesmentioning

confidence: 99%

Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1–infected T cells

Watanabe

2017

Blood

142

117

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“…Stromal cells reduced viral expression via type‐I IFNs, but did not reduce cell growth and even supported it by unknown mechanisms. ( 34,68 )…”

Section: Control Of Htlv‐1 By Innate Immunitymentioning

confidence: 99%

Double control systems for human T‐cell leukemia virus type 1 by innate and acquired immunity

et al. 2011

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Human T‐cell leukemia virus type 1 (HTLV‐1) is the causative retrovirus of adult T‐cell leukemia (ATL) and HTLV‐1‐associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV‐1‐specific T‐cell responses elicit antitumor and antiviral effects in experimental models, and are considered to be one of the most important determinants of the disease manifestation, since they are activated in HAM/TSP but not in ATL patients. The combination of low T‐cell responses and elevated HTLV‐1 proviral loads are features of ATL, and are also observed in a subpopulation of HTLV‐1 carriers at the asymptomatic stage, suggesting that these features may be underlying risk factors. These risks may potentially be reduced by vaccination to activate HTLV‐1‐specific T‐cell responses. HAM/TSP and ATL patients also differ in their levels of HTLV‐1 mRNA expression, which are generally low in vivo but slightly higher in HAM/TSP patients. Our recent study indicated that viral expression in HTLV‐1‐infected T‐cells is suppressed by stromal cells in culture through type‐I IFNs. The suppression was reversible after isolation from the stromal cells, mimicking a long‐standing puzzling phenomenon in HTLV‐1 infection where the viral expression is very low in vivo and rapidly induced in vitro. Collectively, HTLV‐1 is controlled by both acquired and innate immunity in vivo: HTLV‐1‐specific T‐cells survey infected cells, and IFNs suppress viral expression. Both effects would contribute to a reduction in viral pathogenesis, although they may potentially influence or conflict with one another. The presence of double control systems for HTLV‐1 infection provides a new concept for understanding the pathogenesis of HTLV‐1‐mediated malignant and inflammatory diseases. (Cancer Sci 2011; 102: 670–676)

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“…TIG-1 cells and fetal lung fibroblast were obtained from Japanese Collection of Research Bioresources Cell Bank. These cells were used for the primary culture of HTLV-1-infected cells (15).…”

Section: Cellsmentioning

confidence: 99%

CD30 Characterizes Polylobated Lymphocytes and Disease Progression in HTLV-1–Infected Individuals

Nakashima

Yamochi

Watanabe

et al. 2018

Clinical Cancer Research

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Although expression of CD30 is reported in a subset of adult T-cell leukemia/lymphoma cases, its clinicopathologic significance is poorly understood. We aimed to characterize CD30-positive cells and clarify their tumorigenic role in human T-cell lymphotropic virus type 1 (HTLV-1)-infected cells. CD30-positive peripheral blood mononuclear cells from individuals with differing HTLV-1 disease status were characterized, and the role of CD30 signaling was examined using HTLV-1-infected cell lines and primary cells. CD30-positive cells were detected in all samples examined, and the marker was coexpressed with both CD25 and CD4. This cell population expanded in accordance with disease progression. CD30-positive cells showed polylobation, with some possessing "flower cell" features, active cycling, and hyperploidy. CD30 stimulation of HTLV-1-infected cell lines induced these features and abnormal cell division, with polylobation found to be dependent on the activation of PI3K. The results thus link the expression of CD30, which serves as a marker for HTLV-1 disease status, to an active proliferating cell fraction featuring polylobation and chromosomal aberrations. In addition, brentuximab vedotin, an anti-CD30 monoclonal antibody conjugated with auristatin E, was found to reduce the CD30-positive cell fraction. Our results indicate that CD30-positive cells act as a reservoir for tumorigenic transformation and clonal expansion during HTLV-1 infection. The CD30-positive fraction may thus be a potential molecular target for those with differing HTLV-1 disease status. .

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Adhesion-dependent growth of primary adult T cell leukemia cells with down-regulation of HTLV-I p40Tax protein: a novel in vitro model of the growth of acute ATL cells

Cited by 8 publications

References 56 publications

Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1–infected T cells

Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1–infected T cells

Double control systems for human T‐cell leukemia virus type 1 by innate and acquired immunity

CD30 Characterizes Polylobated Lymphocytes and Disease Progression in HTLV-1–Infected Individuals

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