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Lymphoma

BIN1 tumor suppressor regulates Fas/Fas ligand–mediated apoptosis through c-FLIP in cutaneous T-cell lymphoma

Leukemia volume 29, pages 1402–1413 (2015)Cite this article

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Abstract

The bridging integrator 1 (BIN1) tumor suppressor encodes multiple alternatively spliced isoforms implicated in DNA repair, cell-cycle control, apoptosis and membrane dynamics. BIN1 attenuation has been reported in several solid tumors; however, the role of BIN1 in lymphomagenesis remains unexplored. We recently demonstrated that BIN1 transcript levels are significantly downregulated in CD4+CD7− Sezary cells from patients with Sezary syndrome (SS), a subtype of cutaneous T-cell lymphoma (CTCL). We have now demonstrated that restored BIN1 expression in CTCL cells leads to a significant reduction in cell proliferation, an increase in spontaneous and Fas/Fas ligand (Fas/FasL)-induced apoptosis in vitro and inhibition of tumorigenic activity of CTCL cells in vivo. Interestingly, restoration of BIN1 expression in CTCL cells downregulates the expression of c-FLIP, an important inhibitor of Fas/FasL-mediated apoptosis, and activates the caspase cascade; these phenotypes can be rescued by knockdown of BIN1. Importantly, significantly reduced BIN1 expression and increased c-FLIP expression are observed in primary CTCL patient samples, and high BIN1 and low c-FLIP mRNA levels correlate with better survival rate in SS patients. These results indicate that BIN1 regulates Fas/FasL-mediated apoptosis through c-FLIP and that BIN1 deficiency may have an important role in CTCL pathogenesis by causing apoptosis resistance. Thus BIN1 and c-FLIP represent potential therapeutic targets in CTCL.

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Acknowledgements

We thank Terry Fox Laboratory FACS Facility for cell sorting; Dr George Prendergast for BIN1 cDNA plasmids and BIN1 (12A) antibody; Dr Linda Penn for BIN1 12A plasmid; Helena Wang and Josephine Leung for excellent technical assistance; and STEMCELL Technologies for cell culture reagents. This work was supported by grants from the Canadian Institutes of Health Research (CIHR) and Canadian Dermatology Foundation (to YZ), the Leukemia & Lymphoma Society of Canada and in part by CIHR, the Canadian Cancer Society and the Cancer Research Society (to XJ). SE and YH are recipients of CIHR Skin Research Training Center Scholarships. YH is a recipient of the Vanier Canada Graduate Scholarship.

Author Contributions

SE, YZ and XJ developed the concept and designed the experiments; SE performed most experiments and analyzed data; YH generated the Kaplan–Meier curve and assisted with q-RT-PCR on primary SS samples; and MS extracted RNA from MF patient samples. SE and XJ wrote the manuscript and the other authors commented on the manuscript.

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Authors and Affiliations

  1. Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada

    S Esmailzadeh, Y Huang & X Jiang

  2. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada

    S Esmailzadeh & X Jiang

  3. Department of Dermatology and Skin Science, Molecular Medicine Laboratory, University of British Columbia, Vancouver, British Columbia, Canada

    Y Huang, M-W Su & Y Zhou

  4. Chieng Genomics Center, Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada

    Y Huang, M-W Su & Y Zhou

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  1. S Esmailzadeh
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Correspondence to X Jiang.

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Esmailzadeh, S., Huang, Y., Su, MW. et al. BIN1 tumor suppressor regulates Fas/Fas ligand–mediated apoptosis through c-FLIP in cutaneous T-cell lymphoma. Leukemia 29, 1402–1413 (2015). https://doi.org/10.1038/leu.2015.9

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