title: Deficiency of the proapoptotic SAP function in X-linked lymphoproliferative disease aggravates Epstein-Barr virus (EBV) induced mononucleosis and promotes lymphoma development.
abstract: The lack of functional SAP protein, a consequence of mutation or deletion of the SH2D1A gene is the cause of X-linked lymphoproliferative disease (XLP). Others and we have shown that SAP can be involved in apoptosis. Activation induced apoptosis plays a pivotal role in the termination of the lymphocyte proliferation in infectious mononucleosis IM. This mechanism is inefficient in the XLP patients. Primary EBV infection of boys with XLP leads therefore to fulminant, often even fatal disease. In addition, the condition predisposes to considerably elevated incidence of lymphomas. Chromosomal translocation that juxtaposes one of the three immunoglobulin loci to the c-myc proto-oncogene is the hallmark of Burkitt lymphomas (BL), whether they carry the Epstein-Barr Virus (EBV) or not. Ig/myc translocations occur as rare accidents of normal B lymphocyte differentiation. The activated myc would drive the cells to proliferate, however unless protected, the cells become prone to apoptosis. Our results with BL derived cell lines suggest that the fate of the precursor cells is decided by the expression of the proapototic SAP and EBV infection. We found SAP expression in eight of ten EBV carrying, but none of nine EBV negative BL lines. Therefore it seems that the apoptosis prone Ig/myc translocation carrying EBV negative precursors of BL can grow into lymphomas only if they do not express the proapoptotic SAP while SAP expressor, but EBV positive cells can survive and proliferate. This is probably due to the antiapoptotic function of EBNA-1 and the proliferation induced by activated myc.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institute, Stockholm, Sweden. Noemi.Nagy@ki.se
authors.forename: Noemi
authors.initials: N
authors.lastname: Nagy
authors.forename: Eva
authors.initials: E
authors.lastname: Klein
mesh_terms: D000818:Animals; D017209:Apoptosis; D002051:Burkitt Lymphoma / Q000209:etiology* / Q000503:physiopathology; D017353:Gene Deletion; D004854:Herpesvirus 4, Human; D006801:Humans; D007244:Infectious Mononucleosis / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008232:Lymphoproliferative Disorders / Q000276:immunology*; D008297:Male; D000090063:Proto-Oncogene Mas; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein