IL-2/IL-2 Receptor Pathway Plays a Crucial Role in the Growth and Malignant Transformation of HTLV-1-Infected T Cells to Develop Adult T-Cell Leukemia

AbstractOncogenic transformation of CD4+ T cells by human T-cell lymphotropic virus type 1 (HTLV-1) is understood as the initial step to adult T-cell leukemia/lymphoma, a process that is mainly initiated by perturbation of cellular signaling by the viral Tax oncoprotein, a potent transcriptional regulator. In search of novel biomarkers with relevance to oncogenesis, we identified the tumor marker and actin-bundling protein Fascin (FSCN1) to be specifically and strongly up-regulated in both HTLV-1–transformed and adult T-cell leukemia/lymphoma patient-derived CD4+ T cells. Fascin is important for migration and metastasis in various types of cancer. Here we report that a direct link can exist between a single viral oncoprotein and Fascin expression, as the viral oncoprotein Tax was sufficient to induce high levels of Fascin. Nuclear factor-κB signals were important for Tax-mediated transcriptional regulation of Fascin in T cells. This suggests that Fascin up-regulation by Tax contributes to the development of HTLV-1–associated pathogenesis.

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Clinical significance of serum Th1-, Th2- and regulatory T cells-associated cytokines in adult T-cell leukemia/lymphoma: High interleukin-5 and -10 levels are significant unfavorable prognostic factors

International Journal of Cancer ◽

10.1002/ijc.21688 ◽

2006 ◽

Vol 118 (12) ◽

pp. 3054-3061 ◽

Cited By ~ 50

Author(s):

Atsushi Inagaki ◽

Takashi Ishida ◽

Toshihiko Ishii ◽

Hirokazu Komatsu ◽

Shinsuke Iida ◽

...

Keyword(s):

T Cells ◽

Prognostic Factors ◽

T Cell ◽

Regulatory T Cells ◽

Clinical Significance ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Interleukin 5 ◽

Adult T Cell Leukemia

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Induction of the IL-9 gene by HTLV-I Tax stimulates the spontaneous proliferation of primary adult T-cell leukemia cells by a paracrine mechanism

Blood ◽

10.1182/blood-2007-09-113654 ◽

2008 ◽

Vol 111 (10) ◽

pp. 5163-5172 ◽

Cited By ~ 31

Author(s):

Jing Chen ◽

Mike Petrus ◽

Bonita R. Bryant ◽

Vinh Phuc Nguyen ◽

Mindy Stamer ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Ex Vivo ◽

Proximal Promoter ◽

Type I ◽

Dependent Manner ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Spontaneous Proliferation

AbstractThe etiologic agent of adult T-cell leukemia (ATL) is human T cell lymphotropic virus type I (HTLV-I). The HTLV-I protein Tax alters gene expression, including those of cytokines and their receptors, which plays an important role in early stages of ATL. Here we demonstrate that expression of interleukin-9 (IL-9) is activated by Tax via an NF-κB motif in its proximal promoter, whereas IL-9 receptor-α (IL-9Rα) expression is not induced by Tax. However, supporting a role for IL-9/IL-9Rα in ATL, a neutralizing monoclonal antibody directed toward IL-9Rα inhibited ex vivo spontaneous proliferation of primary ATL cells from several patients. Fluorescence-activated cell sorter analysis of freshly isolated peripheral blood mononuclear cells from these patients revealed high level expression of IL-9Rα on their CD14-expressing monocytes. Furthermore, purified T cells or monocytes alone from these patients did not proliferate ex vivo, whereas mixtures of these cell types manifested significant proliferation through a contact-dependent manner. Taken together, our data suggest that primary ATL cells, via IL-9, support the action of IL-9Rα/CD14-expressing monocytes, which subsequently support the ex vivo spontaneous proliferation of malignant T cells. In summary, these data support a role for IL-9 and its receptor in ATL by a paracrine mechanism.

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T Cell Receptor Vβ Staining Identifies the Malignant Clone in Adult T cell Leukemia and Reveals Killing of Leukemia Cells by Autologous CD8+ T cells

PLoS Pathogens ◽

10.1371/journal.ppat.1006030 ◽

2016 ◽

Vol 12 (11) ◽

pp. e1006030 ◽

Cited By ~ 12

Author(s):

Aileen G. Rowan ◽

Aviva Witkover ◽

Anat Melamed ◽

Yuetsu Tanaka ◽

Lucy B. M. Cook ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Cell Receptor ◽

Leukemia Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

T Cell Receptor Vβ

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Possible origin of adult T-cell leukemia/lymphoma cells from human T lymphotropic virus type-1-infected regulatory T cells

Cancer Science ◽

10.1111/j.1349-7006.2005.00080.x ◽

2005 ◽

Vol 96 (8) ◽

pp. 527-533 ◽

Cited By ~ 82

Author(s):

Tomoko Kohno ◽

Yasuaki Yamada ◽

Norihiko Akamatsu ◽

Simeru Kamihira ◽

Yoshitaka Imaizumi ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Virus Type ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Lymphoma Cells ◽

T Lymphotropic Virus ◽

Adult T Cell Leukemia

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Clinical and in vitro resistance to bexarotene in adult T-cell leukemia: loss of RXR-α receptor

Blood ◽

10.1182/blood-2008-03-141424 ◽

2008 ◽

Vol 112 (6) ◽

pp. 2484-2488 ◽

Cited By ~ 7

Author(s):

Julie H. Lin ◽

Ellen J. Kim ◽

Anand Bansal ◽

John Seykora ◽

Stephen K. Richardson ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Peripheral Blood ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

First Case ◽

Induced Apoptosis ◽

Resistant Cells

Abstract The oral rexinoid bexarotene (Targretin) is widely used for treatment of cutaneous T-cell lymphomas (CTCL). We recently reported the first case of adult T-cell leukemia/lymphoma (ATLL) that responded rapidly to combination therapy of bexarotene and interferon (IFN)-α2b with complete clinical response. We demonstrated that bexarotene induced apoptosis of the patient's malignant peripheral blood T-cells in vitro. However, our patient developed skin and nodal relapse 180 days after starting treatment. We now demonstrate that his peripheral blood malignant T cells became resistant to bexarotene-induced apoptosis. We investigated potential mechanisms that may cause aberrations in the retinoid X receptor (RXR) subunits, RXR-α and RXR-β, to account for these findings. Sequence analysis did not reveal acquisition of mutations in the genes encoding RXR-α and RXR-β by resistant cells. We assessed RXR-α and RXR-β expression by Western blot analysis and found that resistant cells had significantly decreased RXR-α expression compared with pretherapy bexarotene-sensitive cells. Our findings indicate that reduced expression of the RXR-α receptor subunit may represent a mechanism for resistance to bexarotene in T-cell malignancies.

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Constitutive Activation of Toll like Receptor Signaling in Adult T-Cell Leukemia Cells.

Blood ◽

10.1182/blood.v108.11.2291.2291 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2291-2291

Author(s):

Takamitsu Mizobe ◽

Junichi Tsukada ◽

Takehiro Higashi ◽

Fumihiko Mouri ◽

Ai Matsuura ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Adaptor Protein ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Constitutive Activation ◽

Adult T Cell Leukemia ◽

Human T Cells

Abstract Human T-cell leukemia virus type I (HTLV-I) is etiologically associated with the development of an aggressive and fatal malignancy of CD4+ T lymphocytes called adult T-cell leukemia (ATL). Constitutive activation of nuclear factor-κB (NF-κB) is a common feature of ATL. Although the mechanism by which NF-κB is spontaneously activated in ATL cells still remains unclear, inhibition of NF-κB activity induces apoptosis, suggesting a central role of NF-κB in their proliferation. Toll like receptors (TLRs) are involved in innate cell activation by conserved structures expressed by microorganisms. Engagement of IL-1R or TLR with their cognate ligands causes an adaptor protein MyD88 to be recruited to the receptor complex, which in turn promotes its association with the IL-1R-associated kinase (IRAK) via an interaction between the respective death domains of each molecule. Several recent reports have indicated unique expression profiles of TLRs on different subsets of human T cells, and that some TLR ligands modulate the function of human T cells. We examined expression of the TLR mRNAs in primary ATL cells and ATL cell lines, MT2, MT4 and HUT102 by RT-PCR. Expression of TLR mRNAs, except of TLR7 and TLR8, was detected in all cell samples examined. We further demonstrated constitutive association of MyD88, an adaptor protein for the TLR signaling, with the IL-1R-associated kinase 1 (IRAK1) in ATL cell lines, MT2, MT4 and HUT102. In MT2 cells, constitutive activation of NF-κB and NF-IL6, but not Stat3 was significantly inhibited by expression of a dominant negative form of MyD88 protein (MyD88dn). Spontaneous transcriptional activation of IL-1α, IFN-γ and TNF-α gene promoters in MT2 cells was also suppressed by MyD88dn expression. MyD88dn inhibited cell proliferation and induced apoptosis of MT2 cells. In addition, overexpression of wild-type MyD88 and HTLV-I Tax induces synergistically transcriptional activity of NF-κB in 293T cells, showing interaction of Tax with MyD88. Thus, our results show a critical role of MyD88 in dysregulated gene activation and cell proliferation in HTLV-I-transformed T-cells, and further suggest the involvement of MyD88 in Tax-mediated intracellular signal transduction in HTLV-I-infected cells. Considering the fact that blocking NF-κB is a potential strategy to treat ATL, our argument raises a possibility that we may be able to find new treatment targets against ATL.

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Molecular Allelo-Karyotyping of Adult T-Cell Leukemia Using High SNP Genotyping Microarrays.

Blood ◽

10.1182/blood.v110.11.2385.2385 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2385-2385

Author(s):

Satsuki Muto ◽

Go Yamamoto ◽

Yasuhito Nannya ◽

Masashi Sanada ◽

Nazanin Dabaghmanesh ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Copy Number ◽

Cell Transformation ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Copy Numbers ◽

Allele Specific

Abstract Adult T cell leukemia/lymphoma (ATL) is a mature T-cell neoplasm in adult that is caused by human T-cell leukemia virus type 1 (HTLV-1) and highly intractable to conventional therapeutics. Since there are 1.2 million HTLV-1 carriers in Japan and more than 50,000 carriers are expected to develop ATL from now on, it is of particular importance to understand the pathogenesis of ATL. The malignant processes of T-cell transformation in ATL are initiated by HTLV-1 infection in early childhood, and the HTLV-1 infected and immortalized T-cells are thought to accumulate a series of genetic hits during the later life, ultimately giving rise to malignant ATL clones after decades of latency periods. However, little is known about the nature of these genetic hits that take place after the early immortalization processes of T-cells mediated by HTLV-1 Tax protein. So in order to clarify the genetic alterations involved in the later processes of T-cell transformation in ATL, we analyzed a total of 130 ATL samples using Affymetrix® GeneChip® 250K Nsp arrays. Combined with CNAG/AsCNAR software, these arrays allow for accurate determination of allele-specific copy numbers in extremely high-resolution (less than 12kb) to detect copy number alterations as well as allelic imbalances in ATL genomes without depending on the availability of constitutive DNA of tumor specimens (molecular allelo-karyotyping). ATL genomes show characteristic copy number profiles and unique patterns of allelic imbalances, which are distinct from acute lymphoblastic ALL and non-Hodgikin’s lymphomas and include gains of 1q arm, 2q33, 3p and 3q arms, 9p12, 17q12, and 19p13, and losses of 1p13.1, 2q end, 3q22, 4q31, 6p22, 7q31, 9p21, 10p14, 12q13, 14q24, and 19q13. Moreover, allele-specific determination of copy numbers disclosed a number of regions showing copy number neutral LOH. Numerous homozygous deletions and gene amplifications were also identified and commonly mapped to less than 500Kb regions, which facilitated identification of candidate gene targets. Interestingly, these genetic lesions involved many T-cell related genes, indicating that the de-regulation of normal T cell functions may contribute the pathogenesis of ATL. In conclusion, molecular allelo-karyotyping of ATL genomes using SNP arrays provides valuable information about the molecular targets in ATL pathogenesis.

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