Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma

Cancer Discov. 2020 Mar;10(3):440-459. doi: 10.1158/2159-8290.CD-19-0116. Epub 2020 Jan 8.


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: (i) growth inhibition of lymphoma cells through induction of BCL6 target genes such as CDKN1A and (ii) restoration of immune surveillance due to induction of BCL6-repressed IFN pathway and antigen-presenting genes. By reactivating these genes, exposure to HDAC3 inhibitors restored the ability of tumor-infiltrating lymphocytes to kill DLBCL cells in an MHC class I and II-dependent manner, and synergized with PD-L1 blockade in a syngeneic model in vivo. Hence, HDAC3 inhibition represents a novel mechanism-based immune epigenetic therapy for CREBBP-mutant lymphomas. SIGNIFICANCE: We have leveraged the molecular characterization of different types of CREBBP mutations to define a rational approach for targeting these mutations through selective inhibition of HDAC3. This represents an attractive therapeutic avenue for targeting synthetic vulnerabilities in CREBBP-mutant cells in tandem with promoting antitumor immunity.This article is highlighted in the In This Issue feature, p. 327.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / drug effects
  • Antigen-Presenting Cells / immunology
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • B7-H1 Antigen / genetics
  • CREB-Binding Protein / genetics*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics*
  • Epigenome / genetics
  • Epigenome / immunology
  • Genes, MHC Class I / immunology
  • Histocompatibility Antigens Class II / immunology
  • Histone Acetyltransferases / genetics
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / drug effects
  • Histone Deacetylases / genetics*
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune System / drug effects
  • Immune System / immunology
  • Interferons / genetics
  • Interferons / immunology
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphoma / drug therapy
  • Lymphoma / genetics*
  • Lymphoma / immunology
  • Lymphoma / pathology
  • Mice
  • Mutation / genetics
  • Proto-Oncogene Proteins c-bcl-6 / genetics*
  • Signal Transduction / drug effects


  • B7-H1 Antigen
  • BCL6 protein, human
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Histocompatibility Antigens Class II
  • Histone Deacetylase Inhibitors
  • Immune Checkpoint Inhibitors
  • Proto-Oncogene Proteins c-bcl-6
  • Interferons
  • CREB-Binding Protein
  • CREBBP protein, human
  • Histone Acetyltransferases
  • Histone Deacetylases
  • histone deacetylase 3