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Non-Hodgkin Lymphoma
Bromodomain and extra-terminal domain inhibition modulates the expression
of pathologically relevant microRNAs
in diffuse large B-cell lymphoma
Afua A. Mensah,1* Luciano Cascione,1,2,3* Eugenio Gaudio,1 Chiara Tarantelli,1 Riccardo Bomben,4 Elena Bernasconi,1 Domenico Zito,5,6 Andrea Lampis,5,6 Jens C. Hahne,5,6 Andrea Rinaldi,1 Anastasios Stathis,3 Emanuele Zucca,3
Ivo Kwee,1,2,7 Valter Gattei,4 Nicola Valeri,5,6 Maria E Riveiro8 and Francesco Bertoni1
1Università della Svizzera italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland; 2Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland; 3Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; 4Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Aviano, Italy; 5The Institute of Cancer Research, London, UK; 6The Royal Marsden NHS Foundation Trust, London and Surrey, UK; 7Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland and 8Oncology Therapeutic Development, Clichy, France.
ABSTRACT
Aberrant changes in microRNA expression contribute to lym- phomagenesis. Bromodomain and extra-terminal domain inhibitors such as OTX015 (MK-8628, birabresib) have demon- strated preclinical and clinical activity in hematologic tumors. 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 chromatin immunoprecipitation sequencing data of diffuse large B-cell lymphoma cells treated with bro- modomain 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 chromatin immunoprecipitation sequencing data revealed that microRNAs downregulated by OTX015 also exhibited reduced BRD4 binding in their promoter regions following treatment with another bro- modomain and extra-terminal domain inhibitor, JQ1, indicating that BRD4 contributes directly 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 modu- lates the transcription of miR-96-5p. The data presented here indicate that in addition to previously observed effects on the expression of cod- ing genes, bromodomain and extra-terminal domain inhibitors also modulate the expression of microRNAs involved in lymphomagenesis.
Introduction
The important role of non-coding elements of the genome, specifically microRNAs (miRNAs), in mediating cellular transformation was first demonstrat- ed in chronic lymphocytic leukemia.1 Since then, numerous miRNAs have been shown to function as tumor suppressors or oncogenes in both hematologic and solid tumors.2-8 miRNAs are short sequences of 19 – 25 nucleotides that function as part of an RNA-induced silencing complex (RISC).9 In humans, they function primarily by destabilizing messenger RNA (mRNA) and inhibiting the translation of mRNA into protein. This is achieved through binding of the 5’ seed region of a
Ferrata Storti Foundation
Haematologica 2018 Volume 103(12):2049-2058
*These authors contributed equally to this work.
Correspondence:
frbertoni@mac.com
Received: February 20, 2018. Accepted: July 31, 2018. Pre-published: August 3, 2018.
doi:10.3324/haematol.2018.191684
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/12/2049
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