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

• Published in: Oncogene Vol. 33; no. 22; pp. 2928 - 2937
• Main Authors: Tolani, B, Gopalakrishnan, R, Punj, V, Matta, H, Chaudhary, P M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.05.2014; Nature Publishing Group
• Subjects: 692/699/67/1059/602; 692/699/67/1858; 692/699/67/1990/291/1621; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Azepines - pharmacology; B-cell lymphoma; c-Myc protein; Cancer; Care and treatment; Cell Biology; Cell Cycle Checkpoints - drug effects; Cell Cycle Proteins; Cell Line, Tumor; Cell Nucleus - metabolism; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell Survival - genetics; Cellular Senescence - drug effects; Chromatin; Chromosome translocations; Development and progression; Disease Models, Animal; Dose-Response Relationship, Drug; Ectopic expression; Effusion; Female; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Gene silencing; Genes; Genomics; Herpes viruses; Herpesvirus; Herpesvirus 8, Human; Heterocyclic Compounds, 4 or More Rings - pharmacology; Human Genetics; Humans; Inhibitory Concentration 50; Internal Medicine; Kaposi's sarcoma; Kaposi's sarcoma-associated herpesvirus; Kaposis sarcoma; Kinases; Lymphocytes B; Lymphoma; Lymphoma, Primary Effusion - genetics; Lymphoma, Primary Effusion - metabolism; Lymphoma, Primary Effusion - pathology; Lymphoma, Primary Effusion - virology; Lymphomas; Medicine; Medicine & Public Health; Myc protein; Nuclear Proteins - antagonists & inhibitors; Oncology; original-article; Post-translation; Primary effusion lymphoma; Properties; Protein Binding - drug effects; Protein Transport; Proteins; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Senescence; Transcription; Transcription Factors - antagonists & inhibitors; Transcription, Genetic; Triazoles - pharmacology; Tumor Burden - drug effects; Tumors; Virus Replication - drug effects; Xenograft Model Antitumor Assays; Xenografts; BET; bromodomain; KSHV; Myc; PEL
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2013.242

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 G 0 /G 1 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.