title: Targeting Myc in KSHV-associated primary effusion lymphoma with BET bromodomain inhibitors.
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.
authors.affiliation: 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.
authors.forename: B
authors.initials: B
authors.lastname: Tolani
authors.affiliation: 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.
authors.forename: R
authors.initials: R
authors.lastname: Gopalakrishnan
authors.affiliation: 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.
authors.forename: V
authors.initials: V
authors.lastname: Punj
authors.affiliation: 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.
authors.forename: H
authors.initials: H
authors.lastname: Matta
authors.affiliation: 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.
authors.forename: P M
authors.initials: PM
authors.lastname: Chaudhary
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D019288:Herpesvirus 8, Human; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D054685:Lymphoma, Primary Effusion / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D014158:Transcription, Genetic; D014230:Triazoles / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D018797:Cell Cycle Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C568713:GSK1210151A