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The BET Bromodomain inhibitor OTX015 (MK-8628) in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance

ABSTRACT: Activity of the BET Bromodomain inhibitor OTX015 (MK8628) in mantle cell lymphoma as single agent and in combination

ORGANISM(S): Homo sapiens

PROVIDER: GSE110134 | GEO | 2018/11/21

REPOSITORIES: GEO

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Project description:Aberrant changes in microRNAs (miRNAs) contribute to lymphomagenesis and represent potential therapeutic targets. OTX015 (MK-8628), a bromodomain and extra-terminal domain (BET) inhibitor (BETi), has demonstrated preclinical and clinical activity in haematological tumours. To better understand the mechanism of action of OTX015 we studied its effects on miRNAs in lymphomas. We performed miRNA profiling of DLBCL cells treated with OTX015 and observed changes in the expression levels of a subset of miRNAs, including miR-92a-1-5p, miR-21-3p, miR-155-5p and miR-96-5p, which are known to play a role in lymphomagenesis and/or resistance to chemotherapy. Analysis of publicly available BRD4 ChIP-Seq data of DLBCL cells treated with the BETi JQ1 showed that BRD4 was bound to the upstream regulatory regions of multiple miRNA genes and that this binding decreased following BETi. Alignment of our miRNA profiling data with the BRD4 ChIP-Seq data revealed that many miRNAs downregulated by OTX015 also exhibited reduced BRD4 binding in their promoter regions following BETi treatment, indicating that BRD4 directly modulated miRNA expression in lymphoma. Among the miRNAs upregulated in response to OTX015 was miR-96-5p, a miRNA known to play a role in B-cell transformation. In lymphomas, miR-96-5p transcription is repressed by the arginine methyltransferase PRMT5. In turn, PRMT5 translation is inhibited by miR-96-5p. We demonstrated that BRD4 bound to the 5’ regulatory region of PRMT5 and that following BET inhibition PRMT5 expression decreased, BRD4 binding to the 5’ region of PRMT5 was reduced and enrichment of PRMT5 at the miR-96-5p promoter lessened. Our results demonstrate that BRD4 binds to the promoters of miRNA genes to directly modulate their expression in lymphoma cells and that BETi administration results in decreased binding of BRD4 to the promoters of specific miRNAs to reduce their expression. Additionally, we show that BETi treatment can affect the expression of genes that control miRNA transcription to indirectly modulate miRNA expression. The data presented here indicate that the ability of BETi to inhibit or activate specific signalling pathways and processes critical to lymphoma cell proliferation and survival is in part due to changes in miRNA expression.

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The BET Bromodomain inhibitor OTX015 (MK-8628) in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance

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