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Clinical application and functional characterization of TOX in cutaneous T-cell lymphoma

University of British Columbia

Cutaneous T-cell lymphoma (CTCL) is a group of lymphoproliferative disorders consisting of two main subtypes: mycosis fungoides (MF) and Sézary syndrome (SS). Due to the lack of robust histological markers, it remains a challenge to establish an accurate diagnosis and offer long term prognostication for CTCL. In addition, the molecular pathogenesis of CTCL is only partially understood. Previously our group discovered that early stage MF skin biopsies contained ectopic expression of TOX gene, which is essential for the early development of CD4⁺ T cells but normally is switched off in mature CD4⁺ T cells in the peripheral tissues. The objectives of my thesis research are to evaluate if TOX can be used to improve CTCL diagnosis and prognostication, and to characterize the functional role of TOX in the pathogenesis of CTCL. Using skin biopsies and clinical databases from Vancouver, Beijing and Boston, I confirmed that TOX expression levels were significantly upregulated in the full spectrum of MF and in SS. In addition, as a diagnostic marker, high TOX expression levels differentiated CTCL from non-CTCL controls with good sensitivity and specificity. Furthermore, as a prognostic marker, high TOX mRNA levels correlated with increased risks of disease progression and disease-specific mortality in MF, and increased risks of disease-specific mortality in SS. I also investigated the functional role of TOX in CTCL pathogenesis using multiple CTCL cell lines and a mouse xenograft model. TOX knockdown in three CTCL cell lines led to markedly increased apoptosis, reduced cell proliferation, and impaired tumorigenic ability. These effects were partially mediated by increased expression of two cell cycle regulators, CDKN1B and CDKN1C. In addition, transcriptome analysis between TOX-suppressed cells and control CTCL cells uncovered additional potential molecules downstream of TOX, such as tumor suppressors FOXO3 and HBP1. Our results provide strong evidence that aberrant activation of TOX can serve as a diagnostic and prognostic biomarker for CTCL. Further, we demonstrated that TOX plays a crucial oncogenic role in CTCL pathogenesis, partially through regulating transcription of CDKN1B, CDKN1C and other downstream genes. Therefore TOX and/or its downstream genes may be promising therapeutic targets for CTCL.

Text

2016-04-20

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/57690

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/