Effects of lymphocyte profile on development of EBV-induced lymphoma subtypes in humanized mice

Abstract

Epstein-Barr virus (EBV) infection causes both Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). The present study reveals that EBV-induced HL and NHL are intriguingly associated with a repopulated immune cell profile in humanized mice. Newborn immunodeficient NSG mice were engrafted with human cord blood CD34+ hematopoietic stem cells (HSCs) for a 8- or 15-wk reconstitution period (denoted 8whN and 15whN, respectively), resulting in human B-cell and T-cell predominance in peripheral blood cells, respectively. Further, novel humanized mice were established via engraftment of hCD34+ HSCs together with nonautologous fetal liver-derived mesenchymal stem cells (MSCs) or MSCs expressing an active notch ligand DLK1, resulting in mice skewed with human B or T cells, respectively. After EBV infection, whereas NHL developed more frequently in B-cell-predominant humanized mice, HL was seen in T-cell-predominant mice (P = 0.0013). Whereas human splenocytes from NHL-bearing mice were positive for EBV-associated NHL markers (hBCL2+, hCD20+, hKi67+, hCD20+/EBNA1+, and EBER+) but negative for HL markers (LMP1-, EBNA2-, and hCD30-), most HL-like tumors were characterized by the presence of malignant Hodgkin's Reed-Sternberg (HRS)-like cells, lacunar RS (hCD30+, hCD15+, IgJ-, EBER+/hCD30+, EBNA1+/hCD30+, LMP+/EBNA2-, hCD68+, hBCL2-, hCD20-/weak, Phospho STAT6+), and mummified RS cells. This study reveals that immune cell composition plays an important role in the development of EBV-induced B-cell lymphoma.