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

Autor:	Mensah AA; Università della Svizzera italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland., Cascione L; Università della Svizzera italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland.; Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland., Gaudio E; Università della Svizzera italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland., Tarantelli C; Università della Svizzera italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland., Bomben R; Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Aviano, Italy., Bernasconi E; Università della Svizzera italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland., Zito D; The Institute of Cancer Research, London, UK.; The Royal Marsden NHS Foundation Trust, London and Surrey, UK., Lampis A; The Institute of Cancer Research, London, UK.; The Royal Marsden NHS Foundation Trust, London and Surrey, UK., Hahne JC; The Institute of Cancer Research, London, UK.; The Royal Marsden NHS Foundation Trust, London and Surrey, UK., Rinaldi A; Università della Svizzera italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland., Stathis A; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland., Zucca E; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland., Kwee I; Università della Svizzera italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland.; Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.; Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland., Gattei V; Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Aviano, Italy., Valeri N; The Institute of Cancer Research, London, UK.; The Royal Marsden NHS Foundation Trust, London and Surrey, UK., Riveiro ME; Oncology Therapeutic Development, Clichy, France., Bertoni F; Università della Svizzera italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland frbertoni@mac.com.
Jazyk:	angličtina
Zdroj:	Haematologica [Haematologica] 2018 Dec; Vol. 103 (12), pp. 2049-2058. Date of Electronic Publication: 2018 Aug 03.
DOI:	10.3324/haematol.2018.191684
Abstrakt:	Aberrant changes in microRNA expression contribute to lymphomagenesis. Bromodomain and extra-terminal domain inhibitors such as OTX015 (MK-8628, birabresib) have demonstrated 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 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 chromatin immunoprecipitation sequencing 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 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 modulates the transcription of miR-96-5p. The data presented here indicate that in addition to previously observed effects on the expression of coding genes, bromodomain and extra-terminal domain inhibitors also modulate the expression of microRNAs involved in lymphomagenesis. (Copyright© 2018 Ferrata Storti Foundation.)
Databáze:	MEDLINE
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