Oncotarget

Research Papers:

Dysregulation of the TOX-RUNX3 pathway in cutaneous T-cell lymphoma

Brittany O. Dulmage _, Oleg Akilov, John R. Vu, Louis D. Falo Jr and Larisa J. Geskin

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Oncotarget. 2019; 10:3104-3113. https://doi.org/10.18632/oncotarget.5742

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Abstract

Brittany O. Dulmage1, Oleg Akilov1, John R. Vu1, Louis D. Falo1, Larisa J. Geskin2

1Department of Dermatology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

2Department of Dermatology, Columbia University, New York, New York, USA

Correspondence to:

Larisa J. Geskin, e-mail: [email protected]

Keywords: cutaneous T-cell lymphoma; Sézary syndrome; gene expression; romidepsin; TOX

Received: June 17, 2015     Accepted: September 18, 2015     Epub: November 06, 2015     Published: May 03, 2019

ABSTRACT

Studies have examined gene expression changes in Sézary syndrome (SS), but disease pathogenesis remains largely unknown, and diagnosis and treatment are difficult. TOX is a transcription factor involved in CD4+ T-cell development with downstream effects on RUNX3, a known tumor suppressor gene. We sought to identify genes involved in SS disease pathogenesis with the potential to enable diagnosis and treatment. We utilized previously reported transcriptome sequencing data to construct a list of candidate genes, which was narrowed using pathway analysis. qRT-PCR confirmed TOX upregulation (>7 fold increase) in SS (n = 5), as well as two established markers, PLS3 and KIRD3DL2. We also evaluated expression of members of the TOX-RUNX3 pathway and confirmed downregulation of RUNX3 (0.59 fold decrease) and upregulation of GATA3 (2 fold increase). Moreover, TOX and RUNX3 expression were significantly inversely proportional. Using siRNA to suppress TOX, we demonstrated that TOX knockdown rescues RUNX3 expression and reduces cell viability. We evaluated TOX protein expression in paraffin-embedded skin biopsies with immunohistochemistry, showing nuclear staining of CTCL infiltrates, suggesting it is a candidate diagnostic biomarker. Further studies validating our findings and evaluating the TOX-RUNX3 pathway and the role of TOX as a disease marker and therapeutic target are warranted.


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