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UBC Theses and Dissertations

The role of BIN1 in the regulation of cell proliferation, apoptosis and tumor formation in cutaneous T-cell lymphoma Esmailzadeh, Sharmin


Cutaneous T-cell lymphomas (CTCLs) represent a group of lymphoproliferative disorders characterized by homing of malignant T-cells to the skin’s surface. There are two main types of CTCL: Mycosis Fungoides (MF) and Sezary Syndrome (SS). We have demonstrated that expression of the Abelson helper integration site-1 (AHI-1) oncogene is significantly increased in CD4⁺CD7- cells from SS patients. Bridging integrator 1 (BIN1) has been identified by microarray analysis of CTCL cells as a candidate gene involved in AHI-1-mediated lymphomagenesis. Interestingly, BIN1expression is significantly reduced in SS patient samples. However, the role of BIN1 and its molecular connection to AHI-1 in lymphomagenesis remains unexplored. I extensively investigated the role of key BIN1 isoforms in primary and CTCL cell line model systems both in vitro and in vivo. I demonstrated that overexpression/restored expression of BIN1 isoforms has strong anti-proliferative and pro-apoptotic roles in CTCL cells in vitro, and significantly inhibits the tumorigenic activity of these cells in vivo. The pro-apoptotic role of BIN1 in CTCL cells occurs through downregulation of c-FLIP, a critical inhibitor of Fas/FasL-mediated apoptosis. I also observed significant reduction and increase in BIN1 and c-FLIP transcripts in primary CTCL samples, respectively. Interestingly, high BIN1 and low c-FLIP transcripts correlated with better survival rate in SS patients. Thus, BIN1 deficiency may play an important role in CTCL pathogenesis by causing apoptosis resistance. Furthermore, I explored potential mechanisms by which AHI-1 leads to downregulation of BIN1, by (1) examining if AHI-1 physically interacts with BIN1; and (2) determining if AHI-1 alters transcription of BIN1 by changing the methylation status of the BIN1 promoter. These experiments did not yield direct evidence of these two potential mechanisms of AHI-1’s role in BIN1 suppression. Thus, the mechanism by which AHI-1 regulates BIN1 remains unknown. Nevertheless, several potential BIN1 interacting proteins were uncovered in CTCL cells, including α/β-tubulin and β-actin. Overall, this study provides the first evidence of strong tumor suppressor activity of BIN1 in CTCL. It points to the loss of BIN1 and subsequent upregulation of c-FLIP as an important mechanism to induce apoptosis resistance in CTCL cells, and identifies BIN1 and c-FLIP as potential CTCL therapeutic targets.

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