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15th Annual Conference of the British HIV Association1-3 April 2009, Liverpool, UK |
METHYLATION REVERSAL IN HIGH GRADE B LYMPHOMA CELL LINES IDENTIFIES NOVEL EPIGENETIC CHANGES CONSERVED BETWEEN IMMUNOCOMPETENT AND HIV-POSITIVE HOSTS AND OTHERS SPECIFIC TO HIV-ASSOCIATED LYMPHOMA
HIV Med 2009 Apr 1-3 (Suppl 1);15:9 (abstract no. O14)
T Crook1, N Syed2, A Papoudou-Bai3, J Stebbing2, K Naresh2, M Nelson1, E Hatzimichael3 and M Bower1
1Chelsea and Westminster Hospital, London, UK, 2Imperial College, London, UK, 3University Hospital of Ioannina, Ioannina, Greece
BACKGROUND: Methylation-dependent transcriptional silencing is an important mechanism of tumour suppressor gene inactivation in neoplasia, including lymphoma.
METHODS: Pharmacological ‘unmasking’ of transcriptionally silenced genes in B lymphoma cell lines was achieved using 5’ deazacytidine ± Trichostatin A and subsequent analysis of mRNA levels on micro-array. Candidate genes thus identified, were further analysed by qPCR, methylation-specific PCR (MSP) and bisulphite sequencing in B lymphoma cell lines and by MSP in clinical samples from sporadic (immunocompetent) (18 cases) and HIV-infected patients (14 cases). Samples in both patient groups were diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma (BL).
RESULTS: We report the identification of 13 novel genes, not previously described in the literature, which are subject to methylation-dependent transcriptional silencing in high-grade lymphoma. The novel genes encode proteins involved in diverse functional classes and include proapoptotic members of the p53 pathway (Scotin), transcriptional regulators (Baz2B) and regulators of telomerase (Smrf2). The frequency of methylation is similar in DLBCL and BL arising in immunocompetent and HIV-infected hosts. A further 5 novel genes were subject to aberrant CpG methylation with apparent specificity for HIV-associated lymphomas.
CONCLUSIONS: We have identified a number of novel genes subject to transcriptional silencing in high-grade B lymphomas. The similar frequency of methylation observed in immunocompetent and HIV positive patients for a subset of these genes implies that these may be fundamental in suppression of lymphomagenesis. In contrast, other genes are methylated only in HIV-associated cases suggesting important functions in the immunocompromised host. We are currently assessing the potential utility of detection of methylated DNA in these genes as candidate biomarkers of outcome in each patient group.
2009-04-01
O14
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