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Diminished microRNA-29b level is associated with BRD4-mediated activation of oncogenes in cutaneous T-cell lymphoma

Rebecca Kohnken, Jing Wen, Bethany Mundy-Bosse, Kathleen McConnell, Ashleigh Keiter, Leah Grinshpun, Alex Hartlage, Max Yano, Betina McNeil, Nitin Chakravarti, Basem William, James E. Bradner, Michael A. Caligiuri, Pierluigi Porcu and Anjali Mishra

Key points

  • CTCL patients have decreased miR-29b levels and increased BRD4 binding occupancy at promoter regions of tumor-associated genes.

  • Therapeutic targeting of miR-29b and BRD4 in CTCL mice results in significantly decreased disease severity and progression.

Abstract

MicroRNA dysregulation is a hallmark of cutaneous T-cell lymphoma (CTCL), a uniformly fatal malignancy of skin-homing CD4+ T-cells for which there are few effective therapies. The role of microRNAs (miRs) in controlling epigenetic modifier-dependent transcriptional regulation in CTCL is unknown. In this study, we characterize a novel miR dysregulation contributing to overexpression of epigenetic reader bromodomain-containing protein 4 (BRD4). Using patient CD4+ T-cells, we show diminished levels of miR-29b compared to healthy donor cells. Patient cells and miR-29b-/- mouse cells reveal an inverse relationship between miR-29b and BRD4, the latter of which is overexpressed in these cells. Chromatin immunoprecipitation and sequencing analysis reveals increased genome-wide BRD4 occupancy at promoter and enhancer regions in CD4+ T-cells from CTCL patients. The cumulative result of BRD4 binding is increased expression of tumor-associated genes such as NOTCH1 and RBPJ, as well as the interleukin-15 (IL-15) receptor complex; the latter enhancing IL-15 autocrine signaling. Furthermore, we confirm the in vivo relevance of this pathway in our IL-15 transgenic mouse model of CTCL by showing that interference with BRD4-mediated pathogenesis, either by restoring miR-29b levels via bortezomib treatment, or directly inhibiting BRD4 binding via JQ1 treatment, prevents progression of CTCL. We therefore describe a novel oncogenic pathway featuring IL-15, miR-29b, and BRD4 in CTCL, and suggest targeting of these components as a potentially effective therapy for CTCL patients.

  • Submitted September 8, 2017.
  • Accepted November 15, 2017.