Bromodomain and extra-terminal domain inhibition modulates the expression of pathologically relevant microRNAs in diffuse large B-cell lymphoma

Afua A Mensah, Luciano Cascione, Eugenio Gaudio, Chiara Tarantelli, Riccardo Bomben, Elena Bernasconi, Domenico Zito, Andrea Lampis, Jens C Hahne, Andrea Rinaldi, Anastasios Stathis, Emanuele Zucca, Ivo Kwee, Valter Gattei, Nicola Valeri, Maria E Riveiro, Francesco Bertoni

Research output: Contribution to journalArticle

Abstract

Aberrant changes in microRNA expression contribute to lymphomagenesis. Bromodomain and extra-terminal domain inhibitors like OTX015 (MK-8628, birabresib) have demonstrated preclinical and clinical activity in haematological tumours. MicroRNA profiling of diffuse large B-cell lymphoma cells treated with OTX015 revealed changes in the expression levels of a limited number of microRNAs, including miR-92a-1-5p, miR-21-3p, miR-155-5p and miR-96-5p. Analysis of publicly available ChIP-Seq data of diffuse large B-cell lymphoma cells treated with bromodomain and extra-terminal domain (BET) inhibitors showed that the BET family member BRD4 bound to the upstream regulatory regions of multiple microRNA genes and that this binding decreased following BET inhibition. Alignment of our microRNA profiling data with the BRD4 ChIP-Seq data revealed that microRNAs downregulated by OTX015 also exhibited reduced BRD4 binding in their promoter regions following treatment with another bromodomain and extra-terminal domain inhibitor, JQ1, indicating that BRD4 directly contributes to microRNA expression in lymphoma. Treatment with bromodomain and extra-terminal domain inhibitors also decreased the expression of the arginine methyltransferase PRMT5, which plays a crucial role in B-cell transformation and negatively modulates the transcription of miR-96-5p. The data presented here indicate that in addition to the previously observed effects on the expression of coding genes, bromodomain and extra-terminal domain inhibitors also modulate the expression of microRNAs involved in lymphomagenesis.

Original languageEnglish
Pages (from-to)2049
Number of pages2058
JournalHaematologica
Volume103
Issue number12
DOIs
Publication statusPublished - Aug 3 2018

Keywords

  • B-cell lymphoma
  • Aggressive Non-Hodgkin's Lymphoma
  • Epigenetics
  • ; Molecular Pharmacology
  • miRNA

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    Mensah, A. A., Cascione, L., Gaudio, E., Tarantelli, C., Bomben, R., Bernasconi, E., Zito, D., Lampis, A., Hahne, J. C., Rinaldi, A., Stathis, A., Zucca, E., Kwee, I., Gattei, V., Valeri, N., Riveiro, M. E., & Bertoni, F. (2018). Bromodomain and extra-terminal domain inhibition modulates the expression of pathologically relevant microRNAs in diffuse large B-cell lymphoma. Haematologica, 103(12), 2049. https://doi.org/10.3324/haematol.2018.191684