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Series GSE142357 Query DataSets for GSE142357
Status Public on Jun 12, 2020
Title Selective inhibition of HDAC3 targets synthetic vulnerabilities and activates immune surveillance in lymphoma
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome. Genes perturbed by CREBBP mutation are direct targets of the BCL6/HDAC3 onco-repressor complex. Accordingly, we show that HDAC3 selective inhibitors reverse CREBBP mutant aberrant epigenetic programming resulting in: a) growth inhibition of lymphoma cells through induction of BCL6 target genes such as CDKN1A and b) restoration of immune surveillance due to induction of BCL6-repressed IFN pathway and antigen presentation genes. By reactivating these genes, exposure to HDAC3-i restored the ability of tumor infiltrating lymphocytes to kill DLBCL cells in an MHC II and MHC I dependent manner, and synergized with PD-L1 blockade in a syngeneic model in vivo. Hence HDAC3-i represents a novel mechanism-based immune-epigenetic therapy for CREBBP mutant lymphomas.
 
Overall design Lymphoma B cell lines transfected with CRISPR gRNAs to induce CREBBP mutation
KDAC001 is an HDAC3 inhibitor.
KDAC005 is the control compound.
 
Contributor(s) Mondello P, Teater M, Melnick AM, Green MR
Citation(s) 31915197
Submission date Dec 19, 2019
Last update date Jun 12, 2020
Contact name Matt Teater
E-mail(s) mrt2001@med.cornell.edu
Organization name Weill Cornell Medical College
Street address 445 E 69th St
City New York
State/province NY
ZIP/Postal code 10021
Country USA
 
Platforms (1)
GPL20301 Illumina HiSeq 4000 (Homo sapiens)
Samples (50)
GSM4226258 Sample_1_RL_WT_gRNA1_H3K27Ac_ChIPseq
GSM4226259 Sample_2_RL_WT_gRNA1_Input_ChIPseq
GSM4226260 Sample_3_RL_WT_gRNA2_H3K27Ac_ChIPseq
Relations
BioProject PRJNA596752
SRA SRP238231

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE142357_RAW.tar 22.0 Mb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file
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