Deficiency of the proapoptotic SAP function in X-linked lymphoproliferative disease aggravates Epstein-Barr (EBV) induced mononucleosis and promotes lymphoma development

Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institute, Stockholm, Sweden.
Immunology letters (Impact Factor: 2.51). 05/2010; 130(1-2):13-8. DOI: 10.1016/j.imlet.2010.01.002
Source: PubMed


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.

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    • "Lymphoproliferative disorders affect 20–30% of patients with XLP (Sumegi et al, 2000; Rezaei et al, 2011). The predisposition to lymphoma in XLP patients probably reflects a combination of immune dysregulation, loss of immune surveillance, and loss of SH2D1A-mediated pro-apoptotic signalling in T-and B-cells (Nagy & Klein, 2010; Rezaei et al, 2011). Many lymphomas are EBV-associated – these occur at an earlier median age than EBV-negative cases and carry a poorer prognosis (Sumegi et al, 2000). "

    Preview · Article · Jul 2013 · British Journal of Haematology
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    • "One patient, BL1, demonstrated a 400 kb hemizygous deletion of the SH2D1A gene at Xq25 in both his tumour and germline DNA, which is diagnostic of X-linked lymphoproliferative disease (XLP). XLP patients are at an approximately 200-fold increased risk for lymphoma, and BL accounts for approximately half of the lymphomas in these patients (Nagy and Klein 2010). This SH2D1A deletion may thus represent the cause of this patient's pBL. "
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