Preclinical Targeting of MicroRNA-214 in Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphomas (CTCLs) are a family of primary extranodal lymphomas of mature CD4+, skin-homing or skin-resident T cells. In a significant fraction of patients with CTCL, the neoplastic CD4+ lymphocytes acquire extracutaneous tropism, and with disease progression, they disseminate to the lymph nodes, peripheral blood, and visceral organs. MicroRNA (miR)-based therapies are a newly emerging strategy for many types of diseases, including cancers. CTCL represents one of the disease indications for a clinical trial of miR inhibitor therapy, supporting further investigation of epigenetic dysregulation and miR-driven oncogenesis in this disease. In this study, we interrogated an aberrant miR-based regulatory network that operates in malignant CD4+ T cells and identified potential targets of therapy. We show that miR-214 levels are significantly higher in purified CD4+ neoplastic T cells from patients with CTCL than from healthy donors. We then show that antagomiR-214 treatment of IL-15 transgenic mice with spontaneous, miR-214-overexpressing CTCL leads to significant decrease in disease severity using multiple validated clinical and histological endpoints, compared with scrambled control-treated IL-15 transgenic CTCL mice. Mechanistically, we show that aberrantly expressed TWIST1 and BET protein BRD4 cooperate to drive miR-214 expression in CTCL cell lines and in samples from patients with CTCL and that treatment with BRD4 inhibitor JQ1 leads to down-regulation of miR-214. Based on both in vitro and in vivo data, we propose that the TWIST1/BRD4/miR-214 regulatory loop is an important, targetable, oncogenic pathway in CTCL.