Preclinical Targeting of MicroRNA-214 in Cutaneous T-cell Lymphoma (CTCL).
Kohnken R, McNeil B, Wen J, McConnell K, Grinshpun L, Keiter A, Chen L, William B, Porcu P, Mishra A
J Invest Dermatol in press 03/12/2019
Cutaneous T-cell lymphomas (CTCL) are a family of primary extranodal lymphomas of mature CD4+, skin-homing or skin-resident T-cells. In a significant fraction of CTCL patients 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 interrogate an aberrant miR-based regulatory network that operates in malignant CD4+ T-cells and identify potential targets of therapy. We show that microRNA-214 (miR-214) levels are significantly higher in purified CD4+ neoplastic T-cells from CTCL patients than from healthy donors. We then show that antagomir-214 treatment of interleukin (IL)-15 transgenic (tg) mice with spontaneous, miR-214-overexpressing CTCL, leads to significant decrease in disease severity using multiple validated clinical and histological endpoints, compared to scrambled control-treated IL-15tg CTCL mice. Mechanistically, we show that aberrantly-expressed basic helix-loop-helix domain-containing transcription factor, TWIST1, and bromodomain and extra terminal (BET) protein BRD4, cooperate to drive miR-214 expression in CTCL cell lines and in CTCL patient samples, 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.Full Text