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BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma

Journal article
Authors Joydeep Bhadury
Lisa M Nilsson
Somsundar Veppil Muralidharan
L. C. Green
Z. L. Li
E. M. Gesner
H. C. Hansen
U. B. Keller
K. G. McLure
Jonas A Nilsson
Published in Proceedings of the National Academy of Sciences of the United States of America
Volume 111
Issue 26
Pages E2721-E2730
ISSN 0027-8424
Publication year 2014
Published at Institute of Clinical Sciences, Department of Surgery
Pages E2721-E2730
Language en
Links dx.doi.org/10.1073/pnas.1406722111
Keywords mouse models, JQ1, vorinostat, Brd2, Brd4, BROMODOMAIN PROTEIN BRD4, HISTONE DEACETYLASE INHIBITORS, ACUTE, LYMPHOBLASTIC-LEUKEMIA, ACUTE MYELOID-LEUKEMIA, B-CELL LYMPHOMA, C-MYC, P-TEFB, TRANSCRIPTIONAL ELONGATION, SELECTIVE-INHIBITION, DISRUPTION
Subject categories Cancer and Oncology, Medical Genetics

Abstract

The bromodomain and extraterminal (BET) domain family of proteins binds to acetylated lysines on histones and regulates gene transcription. Recently, BET inhibitors (BETi) have been developed that show promise as potent anticancer drugs against various solid and hematological malignancies. Here we show that the structurally novel and orally bioavailable BET inhibitor RVX2135 inhibits proliferation and induces apoptosis of lymphoma cells arising in Myc-transgenic mice in vitro and in vivo. We find that BET inhibition exhibits broad transcriptional effects in Myc-transgenic lymphoma cells affecting many transcription factor networks. By examining the genes induced by BETi, which have largely been ignored to date, we discovered that these were similar to those induced by histone deacetylase inhibitors (HDACi). HDACi also induced cell-cycle arrest and cell death of Myc-induced murine lymphoma cells and synergized with BETi. Our data suggest that BETi sensitize Myc-overexpressing lymphoma cells partly by inducing HDAC-silenced genes, and suggest synergistic and therapeutic combinations by targeting the genetic link between BETi and HDACi.

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