EBVcarrying Hematopoetic Malignancies with Type IIa Restricted Viral Gene Expression

The EBV-carrying hematopoetic malignancies with Type IIa restricted viral gene expression, Hodgkin- and nasal NK/T-lymphomas express LMP-1 [14, 15, 26]. This molecule has a multitude of functions and interacts with viral and cellular genes. Accordingly its role is different in the two tumor types. Their shared characteristics are that LMP-1 is instrumental in cooperation with the normal tissue environment. However, while the presence of EBV is not obligatory to the development of the HL pathology, all nasal NK lymphomas carry EBV.

LMP-1 is an integral membrane protein composed of a short cytoplasmic N-terminal, six transmembrane domains and a cytoplasmic C-terminal tail. By self aggregating and engaging signalling intermediates of the TNF-receptors (so called TRAFs) it acts like a constitutively active receptor independently of ligand binding. Through the interaction of its C-terminal cytoplasmic tail with the signaling intermediates TRAFs and TRADD, LMP-1 activates the NF-kappa B (both canonical and non-canonical), the p38/MAPK, the JNK, and the phosphatidylinositol 3 kinase (PI3-K) pathways that in turn results in the expression of multiple cellular genes. These are members of the anti-apoptotic family (A20, Bfl-1, Mcl-1, c-IAP2), cytokines (IL-6, IL-8, IL-10, IL-18), cell surface activation or adhesion molecules

(ICAM-1, SLAM, CD23, CD25, CD40, EGFR) and many others. In vitro overexpression studies have shown that LMP-1 has oncogenic effects in non-lymphoid cells. When expressed in rodent fibroblast cell lines, LMP-1 induced cellular transformation. Transgenic expression of LMP-1 in the B-cells of CD40-deficient mice has provided in vivo proof that LMP-1 mimics partially CD40 signals, since it could induce extrafollicular B-cell differentiation, but not germinal center formation.

The contribution of EBV in the development of HL is indicated by the elevated risk for EBV-positive cases in children with a history of IM [27]. However, the characteristic molecular mechanisms were shown to be shared by the virus positive and negative HL. Significance has been attributed to the activation of the NF-kappa B pathway that occurs in both, though induced by different mechanisms.

For the mechanism of HL development, disturbance of B-cell differentiation is proposed to be decisive [28]. According to their scheme, in the process of somatic hypermutation the faulty B-cells that arise in the germinal center are the progenitor of H-RS cells. While the correctly differentiated cells exit the GC, these "crippled" surface Ig-negative B lymphocytes are eliminated by apoptosis [28]. They may be rescued however by EBV infection for which the functions of LMP-1 and LMP-2a are held responsible.

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