title: Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma.
abstract: 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.
authors.affiliation: Constellation Pharmaceuticals, Cambridge, United States.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Conery
authors.affiliation: Constellation Pharmaceuticals, Cambridge, United States.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Centore
authors.affiliation: Constellation Pharmaceuticals, Cambridge, United States.
authors.forename: Adrianne
authors.identifier: http://orcid.org/0000-0001-5329-782X
authors.initials: A
authors.lastname: Neiss
authors.affiliation: Constellation Pharmaceuticals, Cambridge, United States.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Keller
authors.affiliation: Constellation Pharmaceuticals, Cambridge, United States.
authors.forename: Shivangi
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Constellation Pharmaceuticals, Cambridge, United States.
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Spillane
authors.affiliation: Constellation Pharmaceuticals, Cambridge, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Sandy
authors.affiliation: Constellation Pharmaceuticals, Cambridge, United States.
authors.forename: Charlie
authors.initials: C
authors.lastname: Hatton
authors.affiliation: Constellation Pharmaceuticals, Cambridge, United States.
authors.forename: Eneida
authors.initials: E
authors.lastname: Pardo
authors.affiliation: Constellation Pharmaceuticals, Cambridge, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Zawadzke
authors.affiliation: Constellation Pharmaceuticals, Cambridge, United States.
authors.forename: Archana
authors.initials: A
authors.lastname: Bommi-Reddy
authors.affiliation: Genentech, South San Francisco, United States.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Gascoigne
authors.affiliation: Constellation Pharmaceuticals, Cambridge, United States.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Bryant
authors.affiliation: Constellation Pharmaceuticals, Cambridge, United States.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Mertz
authors.affiliation: Constellation Pharmaceuticals, Cambridge, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Sims
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D009101:Multiple Myeloma / Q000503:physiopathology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors*; D012795:Sialoglycoproteins / Q000037:antagonists & inhibitors*; D000099218:Interferon Regulatory Factor-4
chemical_list: D000970:Antineoplastic Agents; D050881:E1A-Associated p300 Protein; D050835:Interferon Regulatory Factors; D010446:Peptide Fragments; D012795:Sialoglycoproteins; D000099218:Interferon Regulatory Factor-4; C571744:bone sialoprotein (35-62), human; C494360:EP300 protein, human
keywords: CBP; EP300; IRF4; MYC; bromodomain; chromosomes; genes; human; human biology; medicine; myeloma