title: Immunomodulatory drugs target IKZF1-IRF4-MYC axis in primary effusion lymphoma in a cereblon-dependent manner and display synergistic cytotoxicity with BRD4 inhibitors.
abstract: Primary effusion lymphoma (PEL) is an aggressive type of non-Hodgkin lymphoma localized predominantly in body cavities. Kaposi's sarcoma-associated herpes virus (KSHV) is the causative agent of PEL. PEL is an incurable malignancy and has extremely poor prognosis when treated with conventional chemotherapy. Immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide are Food and Drug Administration-approved drugs for the treatment of various ailments. IMiDs display pronounced antiproliferative effect against majority of PEL cell lines within their clinically achievable concentrations, by arresting cells at G0/G1 phase of cell cycle and without any induction of KSHV lytic cycle reactivation. Although microarray examination of PEL cells treated with lenalidomide revealed activation of interferon (IFN) signaling, blocking the IFN pathway did not block the anti-PEL activity of IMiDs. The anti-PEL effects of IMiDs involved cereblon-dependent suppression of IRF4 and rapid degradation of IKZF1, but not IKZF3. Small hairpin RNA-mediated knockdown of MYC enhanced the cytotoxicity of IMiDs. Bromodomain (BRD) and extra-terminal domain (BET) proteins are epigenetic readers, which perform a vital role in chromatin remodeling and transcriptional regulation. BRD4, a widely expressed transcriptional coactivator, belongs to the BET family of proteins, which has been shown to co-occupy the super enhancers associated with MYC. Specific BRD4 inhibitors were developed, which suppress MYC transcriptionally. Lenalidomide displayed synergistic cytotoxicity with several structurally distinct BRD4 inhibitors (JQ-1, IBET151 and PFI-1). Furthermore, combined administration of lenalidomide and BRD4 inhibitor JQ-1 significantly increased the survival of PEL bearing NOD-SCID mice in an orthotopic xenograft model as compared with either agent alone. These results provide compelling evidence for clinical testing of IMiDs alone and in combination with BRD4 inhibitors for PEL.
authors.affiliation: Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, Department of Medicine, 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, Department of Medicine, 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, Department of Medicine, 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, Department of Medicine, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Triche
authors.affiliation: Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, Department of Medicine, Keck School of Medicine, Los Angeles, CA, USA.|Department of Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Chaudhary
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000008:administration & dosage; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D055785:Gene Knockdown Techniques; D006801:Humans; D051740:Ikaros Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D007155:Immunologic Factors / Q000008:administration & dosage; D050835:Interferon Regulatory Factors / Q000096:biosynthesis / Q000235:genetics*; D000077269:Lenalidomide; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D010447:Peptide Hydrolases / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000235:genetics*; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives; D014157:Transcription Factors / Q000235:genetics*; D014230:Triazoles / Q000008:administration & dosage; D044767:Ubiquitin-Protein Ligases; D023041:Xenograft Model Antitumor Assays; D000099218:Interferon Regulatory Factor-4; D000092468:Bromodomain Containing Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001381:Azepines; D018797:Cell Cycle Proteins; D051740:Ikaros Transcription Factor; D007155:Immunologic Factors; D050835:Interferon Regulatory Factors; D000077269:Lenalidomide; D009687:Nuclear Proteins; D010447:Peptide Hydrolases; D016271:Proto-Oncogene Proteins c-myc; D013792:Thalidomide; D014157:Transcription Factors; D014230:Triazoles; D044767:Ubiquitin-Protein Ligases; D000099218:Interferon Regulatory Factor-4; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C502543:CRBN protein, human; C497239:IKZF1 protein, human; C489427:MYC protein, human; C467566:pomalidomide