LMP1 + SLAMF1 high cells are associated with drug resistance in Epstein-Barr virus-positive Farage cells

// Heejei Yoon 1 , Young Hyeh Ko 2 1 Clinical Research Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Correspondence to: Young Hyeh Ko, email: yhko310@skku.edu Heejei Yoon, email: namayoon@gmail.com Keywords: EBV+ DLBCL, LMP1, SLAMF1, CHOP, NF-κB Received: July 20, 2016      Accepted: February 13, 2017      Published: February 21, 2017 ABSTRACT How Epstein-Barr virus (EBV) affects the clinical outcome of EBV-positive diffuse large B-cell lymphoma (DLBCL) remains largely unknown. The viral oncogene LMP1 is at the crux of tumorigenesis and cell survival. Therefore, we examined the association between LMP1 high cells drug resistance. We first assessed SLAMF1 as a surrogate marker for LMP1 high cells. LMP1 and its target gene CCL22 were highly expressed in SLAMF1 high Farage cells. These cells survived longer following treatment with a combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). Genes associated with interferon-alpha, allograft rejection, NF-κB and STAT3 were also overexpressed in the surviving Farage cells. Specifically, CHOP treatment increased IL10, LMP1 and pSTAT3 expression levels in a dose-dependent fashion. Addition of exogenous IL4 greatly increased the levels of LMP1 and pSTAT3, which rendered the Farage cells more resistant to CHOP by up-regulating the anti-apoptotic genes BCL-XL and MCL1. The Farage cells were sensitive to Velcade and STAT3, 5, and 6 inhibitors. Inhibition of NF-κB and STAT3, in combination with CHOP, decreased LMP1 levels and effectively induced cell death in the Farage cells. We suggest that LMP1 high cells are responsible for the poor drug response of EBV+ DLBCL and that perturbation of the NF-κB and STAT signaling pathways increases toxicity in these cells.