Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma
Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple mye...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2016-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/10483 |
| _version_ | 1811200401124360192 |
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| author | Andrew R Conery Richard C Centore Adrianne Neiss Patricia J Keller Shivangi Joshi Kerry L Spillane Peter Sandy Charlie Hatton Eneida Pardo Laura Zawadzke Archana Bommi-Reddy Karen E Gascoigne Barbara M Bryant Jennifer A Mertz Robert J Sims III |
| author_facet | Andrew R Conery Richard C Centore Adrianne Neiss Patricia J Keller Shivangi Joshi Kerry L Spillane Peter Sandy Charlie Hatton Eneida Pardo Laura Zawadzke Archana Bommi-Reddy Karen E Gascoigne Barbara M Bryant Jennifer A Mertz Robert J Sims III |
| author_sort | Andrew R Conery |
| collection | DOAJ |
| description | Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Selective targeting of multiple myeloma cell lines through CBP/EP300 bromodomain inhibition is the result of direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4, which is essential for the viability of myeloma cells, and the concomitant repression of the IRF4 target gene c-MYC. Ectopic expression of either IRF4 or MYC antagonizes the phenotypic and transcriptional effects of CBP/EP300 bromodomain inhibition, highlighting the IRF4/MYC axis as a key component of its mechanism of action. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network. |
| first_indexed | 2024-04-12T02:02:50Z |
| format | Article |
| id | doaj.art-d331aee4f7f14c128cc3a9998e1d79c4 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:02:50Z |
| publishDate | 2016-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-d331aee4f7f14c128cc3a9998e1d79c42022-12-22T03:52:37ZengeLife Sciences Publications LtdeLife2050-084X2016-01-01510.7554/eLife.10483Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myelomaAndrew R Conery0Richard C Centore1Adrianne Neiss2https://orcid.org/0000-0001-5329-782XPatricia J Keller3Shivangi Joshi4Kerry L Spillane5Peter Sandy6Charlie Hatton7Eneida Pardo8Laura Zawadzke9Archana Bommi-Reddy10Karen E Gascoigne11Barbara M Bryant12Jennifer A Mertz13Robert J Sims III14Constellation Pharmaceuticals, Cambridge, United StatesConstellation Pharmaceuticals, Cambridge, United StatesConstellation Pharmaceuticals, Cambridge, United StatesConstellation Pharmaceuticals, Cambridge, United StatesConstellation Pharmaceuticals, Cambridge, United StatesConstellation Pharmaceuticals, Cambridge, United StatesConstellation Pharmaceuticals, Cambridge, United StatesConstellation Pharmaceuticals, Cambridge, United StatesConstellation Pharmaceuticals, Cambridge, United StatesConstellation Pharmaceuticals, Cambridge, United StatesConstellation Pharmaceuticals, Cambridge, United StatesGenentech, South San Francisco, United StatesConstellation Pharmaceuticals, Cambridge, United StatesConstellation Pharmaceuticals, Cambridge, United StatesConstellation Pharmaceuticals, Cambridge, United StatesPharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Selective targeting of multiple myeloma cell lines through CBP/EP300 bromodomain inhibition is the result of direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4, which is essential for the viability of myeloma cells, and the concomitant repression of the IRF4 target gene c-MYC. Ectopic expression of either IRF4 or MYC antagonizes the phenotypic and transcriptional effects of CBP/EP300 bromodomain inhibition, highlighting the IRF4/MYC axis as a key component of its mechanism of action. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network.https://elifesciences.org/articles/10483CBPEP300bromodomainIRF4MYCmyeloma |
| spellingShingle | Andrew R Conery Richard C Centore Adrianne Neiss Patricia J Keller Shivangi Joshi Kerry L Spillane Peter Sandy Charlie Hatton Eneida Pardo Laura Zawadzke Archana Bommi-Reddy Karen E Gascoigne Barbara M Bryant Jennifer A Mertz Robert J Sims III Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma eLife CBP EP300 bromodomain IRF4 MYC myeloma |
| title | Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma |
| title_full | Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma |
| title_fullStr | Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma |
| title_full_unstemmed | Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma |
| title_short | Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma |
| title_sort | bromodomain inhibition of the transcriptional coactivators cbp ep300 as a therapeutic strategy to target the irf4 network in multiple myeloma |
| topic | CBP EP300 bromodomain IRF4 MYC myeloma |
| url | https://elifesciences.org/articles/10483 |
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