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Targeting Myc in KSHV-associated primary effusion lymphoma with BET bromodomain inhibitors

Oncogene volume 33, pages 2928–2937 (2014)Cite this article

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Abstract

Primary effusion lymphoma (PEL) is an aggressive form of non-Hodgkin’s B-cell lymphoma associated with infection by Kaposi’s sarcoma-associated herpes virus (KSHV). (+)-JQ1 and I-BET151 are two recently described novel small-molecule inhibitors of BET bromodomain chromatin-associated proteins that have shown impressive preclinical activity in cancers in which MYC is overexpressed at the transcriptional level due to chromosomal translocations that bring the MYC gene under the control of a super-enhancer. PEL cells, in contrast, lack structural alterations in the MYC gene, but have deregulated Myc protein due to the activity of KSHV-encoded latent proteins. We report that PEL cell lines are highly sensitive to bromodomain and extra-terminal (BET) bromodomain inhibitors-induced growth inhibition and undergo G0/G1 cell-cycle arrest, apoptosis and cellular senescence, but without the induction of lytic reactivation, upon treatment with these drugs. Treatment of PEL cell lines with BET inhibitors suppressed the expression of MYC and resulted in a genome-wide perturbation of MYC-dependent genes. Silencing of BRD4 and MYC expression blocked cell proliferation and cell-cycle progression, while ectopic expression of MYC from a retroviral promoter rescued cells from (+)-JQ1-induced growth arrest. In a xenograft model of PEL, (+)-JQ1 significantly reduced tumor growth and improved survival. Taken collectively, our results demonstrate that the utility of BET inhibitors may not be limited to cancers in which genomic alterations result in extremely high expression of MYC and they may have equal or perhaps greater activity against cancers in which the MYC genomic locus is structurally intact and c-Myc protein is deregulated at the post-translational level and is only modestly overexpressed.

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Acknowledgements

The authors thank Dr James Bradner (Dana-Farber Cancer Institute, Boston, MA, USA) for his generous contribution of (+)- JQ1 and (−)- JQ1, Dr Peter Howley (Harvard University) for BRD4 antibody, Gary Hayward (Johns Hopkins University) for RTA antibody, and Drs Lossos and Ramos from the University of Miami for UM-PEL-1 and UM-PEL-3 cells, respectively. This work was supported by grants from the National Institutes of Health (CA139119, DE019811 and P30CA014089) and STOP Cancer Foundations. Flow cytometry was performed in the USC Flow Cytometry Core Facility that is supported in part by the National Cancer Institute Cancer Center Shared Grant award P30CA014089 and the USC Provost Office Dean’s Development Funds.

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  1. Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, University of Southern California Keck School of Medicine, Los Angeles, CA, USA

    B Tolani, R Gopalakrishnan, V Punj, H Matta & P M Chaudhary

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  1. B Tolani
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Correspondence to P M Chaudhary.

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Tolani, B., Gopalakrishnan, R., Punj, V. et al. Targeting Myc in KSHV-associated primary effusion lymphoma with BET bromodomain inhibitors. Oncogene 33, 2928–2937 (2014). https://doi.org/10.1038/onc.2013.242

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