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.
"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). "
"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. "
[Show abstract][Hide abstract] ABSTRACT: The majority of paediatric Burkitt lymphoma (pBL) patients that relapse will die of disease, but markers for this high-risk subset are unknown. MYC translocations characterize pBL, but additional genetic changes may relate to prognosis and serve as potential biomarkers. We utilized a molecular inversion probe single nucleotide polymorphism assay to perform high resolution, genome-wide copy number analysis on archival formalin-fixed, paraffin-embedded pBL and germline tissues. We identified copy number abnormalities (CNAs) in 18/28 patients (64%) with a total of 62 CNAs that included 32 gains and 30 copy number losses. We identified seven recurrent CNAs including 1q gain (7/28, 25%), 13q gain (3/28, 11%), and 17p loss (4/28, 14%). The minimum common amplified region on 13q was at 13q31 and included the MIR17HG (MIR17-92) locus. Samples with this gain had higher levels of MIR17 RNA and showed a tendency for early relapse. Tumour-specific uniparental disomy was identified in 32% of cases and usually was recurrent. These results demonstrate that high-resolution copy number analysis can be performed on archival lymphoma tissue specimens, which has significance for the study of rare diseases.
British Journal of Haematology 11/2011; 155(4):477-86. DOI:10.1111/j.1365-2141.2011.08883.x · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 16-year-old, previously healthy girl presents with a several-day history of fever, sore throat, and malaise. She appears very tired and has a temperature of 39°C. A physical examination is remarkable for diffuse pharyngeal erythema with moderately enlarged tonsils and the presence of several enlarged, tender anterior and posterior cervical lymph nodes. How should this case be managed?
New England Journal of Medicine 05/2010; 362(21):1993-2000. DOI:10.1056/NEJMcp1001116 · 55.87 Impact Factor
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