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

Significance The mechanism of how Epstein-Barr virus (EBV) contributes to the development of two distinct lymphomas remains unknown. Intriguingly, EBV-associated Hodgkin’s lymphoma was seen exclusively in mice with activated T-cell conditions, whereas EBV-associated non-Hodgkin’s lymphoma was developed in mice with suppressed T-cell conditions, in which immature B cells were predominant at the time of EBV infection. This distinct association provides new insight into the pathogenesis of specific types of EBV-induced lymphomas. 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.

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