Lenalidomide, Thalidomide, and Pomalidomide Reactivate the Epstein-Barr Virus Lytic Cycle through Phosphoinositide 3-Kinase Signaling and Ikaros Expression.
OBJECTIVE
Lenalidomide, thalidomide, and pomalidomide (LTP) are immunomodulatory agents approved for use in multiple myeloma, but in some settings, especially with alkylating agents, an increase in Hodgkin lymphoma and other secondary primary malignancies (SPM) has been noted. Some of these malignancies have been linked to Epstein-Barr virus (EBV), raising the possibility that immunomodulatory drugs disrupt latent EBV infection.


METHODS
We studied the ability of LTP to reactivate latently infected EBV-positive cell lines in vitro and in vivo, and evaluated the EBV viral load in archived serum samples from patients who received a lenalidomide, thalidomide, and dexamethasone (LTD) combination.


RESULTS
Treatment of EBV-infected B-cell lines with LTP at physiologically relevant concentrations induced the immediate early gene BZLF1, the early gene BMRF1, and the late proteins VCA and BCFR1. This occurred in the potency order pomalidomide > lenalidomide > thalidomide, and the nucleoside analogue ganciclovir enhanced the cytotoxic effects of lenalidomide and pomalidomide in Burkitt lymphoma cells in vitro and in vivo EBV reactivation was related to PI3K stimulation and Ikaros suppression, and blocked by the PI3Kδ inhibitor idelalisib. Combinations of lenalidomide with dexamethasone or rituximab increased EBV reactivation compared with lenalidomide alone and, importantly, lenalidomide with melphalan produced even greater reactivation.


CONCLUSIONS
We conclude LTP may reactivate EBV-positive resting memory B cells thereby enhancing EBV lytic cycle and host immune suppression. Clin Cancer Res; 22(19); 4901-12. ©2016 AACR.
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas. rjones@mdanderson.org.
Richard J
RJ
Jones
National Nanotechnology Center (NANOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani, Thailand.
Tawin
T
Iempridee
Urology Department, ShengJing Hospital, China Medical University, ShenYang, China.
Xiaobin
X
Wang
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Hans C
HC
Lee
McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
Janet E
JE
Mertz
McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
Shannon C
SC
Kenney
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Heather C
HC
Lin
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Veerabhadran
V
Baladandayuthapani
Birmingham Cancer Research UK Cancer Centre, School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
Christopher W
CW
Dawson
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jatin J
JJ
Shah
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Donna M
DM
Weber
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Robert Z
RZ
Orlowski
D000818:Animals; D045744:Cell Line, Tumor; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D004854:Herpesvirus 4, Human / Q000187:drug effects; D006801:Humans; D051740:Ikaros Transcription Factor / Q000378:metabolism; D007155:Immunologic Factors / Q000009:adverse effects*; D000077269:Lenalidomide; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000821:virology; D016609:Neoplasms, Second Primary / Q000821:virology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D013792:Thalidomide / Q000009:adverse effects / Q000031:analogs & derivatives; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*
C497239:IKZF1 protein, human; D007155:Immunologic Factors; D051740:Ikaros Transcription Factor; D013792:Thalidomide; C467566:pomalidomide; D019869:Phosphatidylinositol 3-Kinases; D000077269:Lenalidomide