Publication Date:
2012-11-16
Description:
Abstract 296 Background: In diffuse large B-cell lymphoma (DLBCL), a number of studies have shown that dual disruption of the p16/Rb and the ARF/p53 pathway, e.g. deletion of the INK4A/ARF locus, are negative prognostic factors for survival. Molecular studies have shown that the p53-miR34 axis may be another link between the ARF/p53 pathway and the p16/Rb pathway. In a complex circuit, p53 promotes transcription of MIR34A and MIR34B/C, and the miR34s' in turn act as mediators of p53 signaling. In addition, miR34s' have been shown to inhibit MYC and several proto-oncogens that counteract the p16/Rb tumor suppressor pathway. These observations place the miR34s' at the center of cell cycle and apoptosis regulation, and loss of miR34 expression has been associated with adverse response to therapy in several tumor types. In CLL it has been suggested that miR34A expression is a surrogate marker for TP53 disruption and the MDM2 SNP309 GG genotype, both associated with a poor prognosis. Design and methods: In CD19+ B-cells isolated from healthy donors (PBL-B) and reactive lymph nodes, the expression of the –5p and –3p species of miR34A, miR34B, and miR34C was analysed by qRT-PCR using LNA-based primers from Exiqon that discriminate the individual miR34 members. Histone H3K4 and H3K27 methylation status at the MIR34A and MIR34B/C promoters was analyzed by ChIP. In 120 newly diagnosed DLBCLs we studied the combined status of TP53 mutations, MIR34A and MIR34B/C promoter DNA methylation, and the MDM2SNP309 GG genotype using a panel of PCR based methods. Results: We initially determined the expression of the individual miR34 family members in PBL-B and in reactive lymph nodes. While miR34A-5p was expressed at low levels in normal PBL-B, no expression of miR34A-3p, miR34B-5p, miR34B-3p, miR34C-5p, and miR34C-3p was observed. In reactive lymph nodes the expression of miR34A-5p was induced in average 70 fold (P
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine