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Immunomodulatory drugs target IKZF1-IRF4-MYC axis in primary effusion lymphoma in a cereblon-dependent manner and display synergistic cytotoxicity with BRD4 inhibitors

Oncogene volume 35, pages 1797–1810 (2016)Cite this article

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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.

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Acknowledgements

We thank the following investigators for their generous gift of cell lines: Dr Jae Jung (BC-3, BCBL-1, JSC-1, BC-1, BCP-1, VG-1 and APK-1); Drs Izidore Lossos and Juan Ramos (UMPEL-1 and UMPEL-3); Dr Art Shaffer (TMD8, U-2932, HBL-1, OCI-Ly7, OCI-Ly8 and OCI-Ly19); Dr Alan Epstein (DG-75); Randall Rossi (SUDHL-4, SUDHL-6, Granta, Toledo, KG-1 and MV-4-11); Dr Markus Mapara (L428, L540, L1236 and KM-H2); Dr Irene Ghobrial (BCWM.1 and WMCL-1); and Dr Alan Lichenstein (MM.1S and RPMI8226). We are grateful to Dr William Kaelin Jr for providing the shRNA constructs (CRBN, IKZF1-1 and IKZF1-2), Dr James Bradner for his generous contribution of (+) and (−) JQ-1, Dr Peter Howley for BRD4 antibody and Dr Gary Hayward for KSHV replication and transcription activator antibody. This work was supported by grants from the National Institutes of Health (CA139119, DE019811, SC CTSI UL1TR000130 and P30CA014089) and Stop Cancer Foundation. Flow Cytometry was analyzed 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. B Tolani

    Present address: 3Current address: Department of Surgery, School of Medicine, University of California at San Francisco, San Francisco, CA, USA.,

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  1. 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

    R Gopalakrishnan, H Matta, B Tolani, T Triche Jr & P M Chaudhary

  2. Department of Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    P M Chaudhary

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RG and PMC are inventors on a patent application (No. 62/031,053) filed to US patent office pertaining to the compositions and methods for treating primary effusion lymphoma. All other authors declare no conflict of interest.

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Microarray gene expression data has been deposited under accession number GSE60618 at the website Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/).

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Gopalakrishnan, R., Matta, H., Tolani, B. et al. Immunomodulatory drugs target IKZF1-IRF4-MYC axis in primary effusion lymphoma in a cereblon-dependent manner and display synergistic cytotoxicity with BRD4 inhibitors. Oncogene 35, 1797–1810 (2016). https://doi.org/10.1038/onc.2015.245

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