Selective inhibition of HDAC3 targets synthetic vulnerabilities and activates immune surveillance in lymphoma

Patrizia Mondello, Saber Tadros, Matt Teater, Lorena Fontan, Aaron Y. Chang, Neeraj Jain, Haopeng Yang, Shailbala Singh, Hsia Yuan Ying, Chi Shuen Chu, Man Chun John Ma, Eneda Toska, Stefan Alig, Matthew Durant, Elisa de Stanchina, Sreejoyee Ghosh, Anja Mottok, Loretta Nastoupil, Sattva S. Neelapu, Oliver WeigertGiorgio Inghirami, José Baselga, Anas Younes, Cassian Yee, Ahmet Dogan, David A. Scheinberg, Robert G. Roeder, Ari M. Melnick, Michael R. Green

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)440-459
Number of pages20
JournalCancer discovery
Volume10
Issue number3
DOIs
StatePublished - Mar 2020

ASJC Scopus subject areas

  • Oncology

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