Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma
- 8 January 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 10 (3), 440-459
- https://doi.org/10.1158/2159-8290.cd-19-0116
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: 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 inhibitor 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.Other Versions
Funding Information
- HHS | NIH | National Cancer Institute (CA201380)
- HHS | NIH | National Cancer Institute (CA055349)
- HHS | NIH | National Cancer Institute (CA192937)
- HHS | NIH | National Cancer Institute (CA016672)
- HHS | NIH | National Cancer Institute (CA008748)
- HHS | NIH | National Cancer Institute (CA178765)
This publication has 48 references indexed in Scilit:
- The Two Faces of Interferon-γ in CancerClinical Cancer Research, 2011
- Inactivating mutations of acetyltransferase genes in B-cell lymphomaNature, 2011
- CREBBP mutations in relapsed acute lymphoblastic leukaemiaNature, 2011
- Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphomaBlood, 2010
- Overlapping functions of Hdac1 and Hdac2 in cell cycle regulation and haematopoiesisThe EMBO Journal, 2010
- Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphomaAnnals of Oncology, 2008
- Germinal-Center Organization and Cellular DynamicsImmunity, 2007
- Global transcriptional coactivators CREB-binding protein and p300 are highly essential collectively but not individually in peripheral B cellsBlood, 2006
- BCL6 interacts with the transcription factor Miz-1 to suppress the cyclin-dependent kinase inhibitor p21 and cell cycle arrest in germinal center B cellsNature Immunology, 2005
- Loss of MHC class II gene and protein expression in diffuse large B-cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: a follow-up study from the Leukemia and Lymphoma Molecular Profiling ProjectBlood, 2004