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

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Date
2018-12
ICR Author
Hahne, Jens
Lampis, Andrea
Valeri, Nicola
Author
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
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Type
Journal Article
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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.
URI
https://repository.icr.ac.uk/handle/internal/2934
DOI
https://doi.org/10.3324/haematol.2018.191684
Collections
  • Molecular Pathology
Subject
Cell Line, Tumor
Humans
Acetanilides
Heterocyclic Compounds, 3-Ring
Cell Cycle Proteins
Nuclear Proteins
Transcription Factors
MicroRNAs
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Protein Binding
Lymphoma, Large B-Cell, Diffuse
Protein Domains
Research team
Evolutionary Genomics & Modelling
Gastrointestinal Cancer Biology and Genomics
Language
eng
Date accepted
2018-07-31
License start date
2018-12
Citation
Haematologica, 2018, 103 (12), pp. 2049 - 2058

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