NeoplasticMiR-17˜92deregulation at a dna fragility motif (SIDD)

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Abstract

Chromosomal or mutational activation ofBCL6(at 3q27) typifies diffuse large B-cell lymphoma (DLBCL) which in the germinal center subtype may be accompanied by focal amplification of chromosome band 13q31 effecting upregulation ofmiR-17˜92. Using long distance inverse-polymerase chain reaction, we mapped and sequenced six breakpoints of a complexBCL6rearrangement t(3;13)(q27;q31)t(12;13)(p11;q31) in DLBCL cells, which placesmiR-17˜92antisense within the resultingITPR2-BCL6chimeric fusion gene rearrangement.MiR-17˜92members were upregulated ˜15-fold over controls in a copy number independent manner consistent with structural deregulation.MIR17HGandITPR2-BCL6were, despite their close configuration, independently expressed, discounting antisense regulation.MIR17HGin t(3;13)t(12;13) cells proved highly responsive to treatment with histone deacetylase inhibitors implicating epigenetic deregulation, consistent with which increased histone-H3 acetylation was detected by chromatin immunoprecipitation near the upstreamMIR17HGbreakpoint. Remarkably, 5/6 DNA breaks in the t(3;13)t(12;13) precisely cut at stress-induced DNA duplex destabilization (SIDD) peaks reminiscent of chromosomal fragile sites, while the sixth lay 150 bp distant. Extended SIDD profiling showed that additional oncomiRs also map to SIDD peaks. Fluorescence in situ hybridization analysis showed that 11 of 52 (21%) leukemia-lymphoma (L-L) cell lines with 13q31 involvement bore structural rearrangements at/nearMIR17HGassociated with upregulation. As well as fueling genome instability, SIDD peaks mark regulatory nuclear-scaffold matrix attachment regions open to nucleosomal acetylation. Collectively, our data indict a specific DNA instability motif (SIDD) in chromosome rearrangement, specifically alterations activatingmiR-17˜92epigenetically via promoter hyperacetylation, and supply a model for the clustering of oncomiRs near cancer breakpoints.

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