Inducible expression and pathophysiologic functions of T-plastin in cutaneous T-cell lymphoma

Bégué, Elodie; Jean-Louis, Francette; Bagot, Martine; Jauliac, Sébastien; Cayuela, Jean‐Michel; Laroche, Liliane; Parquet, Nathalie; Bachelez, Hervé; Bensussan, Armand; Courtois, Gilles; Michel, Laurence

doi:10.1182/blood-2011-09-379156

Cited by 32 publications

(24 citation statements)

References 48 publications

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“…Similarly, overexpression of GATA6 has been implicated in oncogenesis by increasing the Wnt signaling pathway (Zhong et al, 2011). Finally, a recent study suggested that PLS3 overexpression confers anti-apoptotic properties to T cells along with an increase in their migration properties (Begue et al, 2012). Thus, PLS3 overexpression may have implications for the survival and trafficking of T cells in SS.…”

Section: Discussionmentioning

confidence: 95%

Promoter-Specific Hypomethylation Is Associated with Overexpression of PLS3 , GATA6 , and TWIST1 in the Sezary Syndrome

Wong

Gibson

Hake

et al. 2015

Journal of Investigative Dermatology

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The Sézary Syndrome (SS) is an aggressive CD4+ leukemic variant of cutaneous T-cell lymphoma. Epigenetic modification of cancer cell genome is often linked to the expression of important cancer-related genes. Here we addressed the hypothesis that, in SS, DNA hypomethylation is involved in upregulation of PLS3, GATA6, and TWIST1, genes that are undetected in normal lymphocytes. Pyrosequencing analysis of CpG rich regions, and CpG dinucleotides within the 5' regulatory regions, confirmed hypomethylation of all three genes in SS, compared with controls. We then studied how methylation regulates PLS3 transcription in vitro using PLS3-negative (Jurkat) and PLS3-positive (HT-1080) cell lines. Treatment with the hypomethylating agent 5-azacytidine induced PLS3 expression in Jurkat cells and in vitro methylation of the cloned PLS3 promoter suppressed luciferase expression in HT-1080 cells. In conclusion, we show that promoter hypomethylation is associated with PLS3, GATA6, and TWIST1 overexpression in SS CD4+ T cells and that methylation can regulate PLS3 expression in vitro. The mechanisms of DNA hypomethylation in vivo and the functional role of PLS3, TWIST1, and GATA6 in SS are being investigated.

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Section: Discussionmentioning

confidence: 95%

Promoter-Specific Hypomethylation Is Associated with Overexpression of PLS3 , GATA6 , and TWIST1 in the Sezary Syndrome

Wong

Gibson

Hake

et al. 2015

Journal of Investigative Dermatology

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“…This may explain the highly reduced STAT-4 expression in CD164 − CD4 + T cells from B2 patients compared with close to normal expression of STAT-4 in CD164 − CD4 + T cells from B1 patients. It is also possible that some of CD164 − CD4 + T cells are normal T cells activated by malignant cells and as such, they may express various molecules including T plastin or miR-214, that have been shown to be upregulated in activated T cells [4, 20]. Whether the expression of malignancy associated genes in CD164 − CD4 + T cells results from the direct effect of factor (s) triggering malignant transformation or results from factor (s) released by CD164 + CD4 + malignant T cells, remains to be established…”

Section: Discussionmentioning

confidence: 99%

CD164 identifies CD4+ T cells highly expressing genes associated with malignancy in Sézary syndrome: the Sézary signature genes, FCRL3, Tox, and miR-214

et al. 2016

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Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), is associated with a significantly shorter life expectancy compared to skin–restricted mycosis fungoides. Early diagnosis of SS is therefore key to achieving enhanced therapeutic responses. However, the lack of a biomarker (s) highly specific for malignant CD4+ T cells in SS patients has been a serious obstacle in making an early diagnosis. We recently demonstrated the high expression of CD164 on CD4+ T cells from Sézary syndrome patients with a wide range of circulating tumor burdens. To further characterize CD164 as a potential biomarker for malignant CD4+T cells, CD164+ and CD164− CD4+ T cells isolated from patients with high circulating tumor burden, B2 stage, and medium/low tumor burden, B1-B0 stage, were assessed for the expression of genes reported to differentiate SS from normal controls, and associated with malignancy and poor prognosis. The expression of Sézary signature genes: T plastin, GATA-3, along with FCRL3, Tox and miR -214 was significantly higher, whereas STAT-4 was lower, in CD164+ compared with CD164−CD4+ T cells. While Tox was highly expressed in both B2 and B1-B0 patients, the expression of Sézary signature genes, FCRL3 and miR-214 was associated predominantly with advanced B2 disease. High expression of CD164 mRNA and protein was also detected in skin from CTCL patients. CD164 was co-expressed with KIR3DL2 on circulating CD4+ T cells from high tumor burden SS patients, further providing strong support for CD164 as a disease relevant surface biomarker.

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“…Q-PCR reactions were performed with the Power SYBR Green PCR master mix in a MicroAmp optical 96-well reaction plate according to the manufacturer's instructions (Applied Biosystems). Gene expression levels were normalized by β2-microglobulin expression and expressed as 2-ΔCT (Arbitrary Units) as previously described [7].…”

Section: Methodsmentioning

confidence: 99%

“…We recently showed that T-plastin synthesis could be induced by calcium entry and regulated by the calcineurin/NFAT pathway in tumor T cells from patients with Sezary Syndrome [7]. Specific T-plastin upregulation favored tumor T cell migration that was downregulated by calcineurin inhibitors, including CspA or FK506 (Tacrolimus).…”

Section: Introductionmentioning

confidence: 99%

T-Plastin Expression Downstream to the Calcineurin/NFAT Pathway Is Involved in Keratinocyte Migration

et al. 2014

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Cutaneous wound healing requires keratinocyte proliferation, migration and differentiation to restore the barrier function of the skin. The calcineurin/nuclear factor of activated-T-cell (NFAT) signaling pathway has been recently shown to be involved in keratinocyte growth, differentiation and migration. It is induced by an increased intracellular calcium rate and its inhibition results in decreased capacities of keratinocytes to migrate. Nevertheless, the link between calcineurin activation and keratinocyte migration remains unknown. Recently, Orai1, a pore subunit of a store-operated calcium channel that favors calcium influx, was shown to play a critical role to control proliferation and migration of basal keratinocytes. Of interest, the actin-bundling T-plastin is crucial in cell motility through cross-linking to actin filament and its synthesis was shown to be induced by calcium influx and regulated by the calcineurin/NFAT pathway in tumor Sezary cells. We investigated herein the role of the calcineurin/NFAT pathway-dependent T-plastin in keratinocyte migration, by quantifying T-plastin expression in keratinocytes and by analyzing their migration under calcineurin inhibition or knockdown of NFAT2 or T-plastin. We did confirm the role of the calcineurin/NFAT pathway in keratinocyte migration as shown by their decreased capacities to migrate after FK506 treatment or siNFAT2 transfection in both scratching and Boyden assays. The expression of NFAT2 and T-plastin in keratinocytes was decreased under FK506 treatment, suggesting that T-plastin plays a role in keratinocyte migration downstream to the calcineurin/NFAT pathway. Accordingly, siRNA knockdown of T-plastin expression also decreased their migration capacities. Actin lamellipodia formation as well as FAK and β6-integrin expression were also significantly decreased after treatment with FK506 or siRNA, reinforcing that NFAT2-dependent T-plastin expression plays a role in keratinocyte migration. These results indicate that T-plastin might be considered as a major actor in the mechanisms underlying calcineurin/NFAT-dependent keratinocyte migration and may explain wound-healing defects observed in patients under calcineurin inhibitor long-term treatment.

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Inducible expression and pathophysiologic functions of T-plastin in cutaneous T-cell lymphoma

Cited by 32 publications

References 48 publications

Promoter-Specific Hypomethylation Is Associated with Overexpression of PLS3 , GATA6 , and TWIST1 in the Sezary Syndrome

Promoter-Specific Hypomethylation Is Associated with Overexpression of PLS3 , GATA6 , and TWIST1 in the Sezary Syndrome

CD164 identifies CD4+ T cells highly expressing genes associated with malignancy in Sézary syndrome: the Sézary signature genes, FCRL3, Tox, and miR-214

T-Plastin Expression Downstream to the Calcineurin/NFAT Pathway Is Involved in Keratinocyte Migration

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