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

Abstract

MicroRNA (miRNA) dysregulation is a hallmark of cutaneous T-cell lymphoma (CTCL), an often-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 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 and, 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.

Molecular pathogenesis of cutaneous lymphomas

“…The cumulative result of BRD binding is increased expression of tumor‐associated genes, such as NOTCH1 and RBTJ, as well as the interleukin‐15 (IL‐15) receptor complex, the latter enhancing IL‐15 autocrine signalling. Kohnken et al described herewith a novel oncogenic pathway featuring IL‐15, miR‐29B and BRD4 in CTCL, suggesting targeting these components as a potential effective therapy for CTCL patients …”

Preclinical Studies Support Combined Inhibition of BET Family Proteins and Histone Deacetylases as Epigenetic Therapy for Cutaneous T-Cell Lymphoma

“…In preliminary studies published in abstract form, BRD4 was reported to be highly expressed in CTCL, and IL-15 increased it, while miR29b decreased it [25], [26]. In various tumor systems, cytokines and receptors increased by BRD4 include IL-1α, IL-1β, IL-15Rα, IL-15Rβ, and IL-15Rγ [26], [27].…”

TPD7 inhibits the growth of cutaneous T cell lymphoma H9 cell through regulating IL‐2R signalling pathway

“…Cutaneous T cell lymphoma (CTCL) is a kind of extranodal non‐Hodgkin T cell lymphoma characterized by the presence of malignant T cells in the skin. Among various forms of CTCLs, mycosis fungoides (MF) and the leukaemic variant Sézary syndrome (SS) are the most prevalent forms of CTCL . Although some induction chemotherapies have been approved for the treatment of CTCL, the responses of many patients are typically short‐lived .…”

“…Among various forms of CTCLs, mycosis fungoides (MF) and the leukaemic variant Sézary syndrome (SS) are the most prevalent forms of CTCL. 1,2 Although some induction chemotherapies have been approved for the treatment of CTCL, the responses of many patients are typically short-lived. 3 Therefore, developing effective chemotherapies for CTCL is extremely urgent.…”