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

In this study, we characterize a novel miR dysregulation that contributes to overexpression of the epigenetic reader bromodomain-containing protein 4 (BRD4). We used patient CD4+ T cells to show diminished levels of miR-29b compared with healthy donor cells. Patient cells and miR-29b–/– mouse cells revealed an inverse relationship between miR-29b and BRD4, the latter of which is overexpressed in these cells. Chromatin immunoprecipitation and sequencing analysis revealed increased genome-wide BRD4 occupancy at promoter and enhancer regions in CD4+ T cells from CTCL patients. The cumulative result of BRD4 binding was 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 by directly inhibiting BRD4 binding via JQ1 treatment, prevents progression of CTCL. We 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.

Source: Blood - February 15, 2018 Category: Hematology Authors: Kohnken, R., Wen, J., Mundy-Bosse, B., McConnell, K., Keiter, A., Grinshpun, L., Hartlage, A., Yano, M., McNeil, B., Chakravarti, N., William, B., Bradner, J. E., Caligiuri, M. A., Porcu, P., Mishra, A. Tags: Lymphoid Neoplasia Source Type: research