Bromodomain and extra-terminal domain inhibition modulates the expression of pathologically relevant microRNAs in diffuse large B-cell lymphoma.
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ICR Authors
Authors
Mensah, AA
Cascione, L
Gaudio, E
Tarantelli, C
Bomben, R
Bernasconi, E
Zito, D
Lampis, A
Hahne, JC
Rinaldi, A
Stathis, A
Zucca, E
Kwee, I
Gattei, V
Valeri, N
Riveiro, ME
Bertoni, F
Cascione, L
Gaudio, E
Tarantelli, C
Bomben, R
Bernasconi, E
Zito, D
Lampis, A
Hahne, JC
Rinaldi, A
Stathis, A
Zucca, E
Kwee, I
Gattei, V
Valeri, N
Riveiro, ME
Bertoni, F
Document Type
Journal Article
Date
2018-11-30
Date Accepted
2018-07-31
Abstract
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.
Citation
Haematologica, 2018, 103 (12), pp. 2049 - 2058
Source Title
Publisher
FERRATA STORTI FOUNDATION
ISSN
0390-6078
eISSN
1592-8721
Collections
Research Team
Evolutionary Genomics & Modelling
Gastrointestinal Cancer Biology and Genomics
Gastrointestinal Cancer Biology and Genomics