Genomic Analysis News

CBMi Contributes to Article in Blood

The c-Myc oncoprotein regulates greater than 15% of the human transcriptome and a limited number of microRNAs. Here we establish that in a human B-lymphoid cell line Myc-repressed, but not Myc-stimulated, genes are significantly enriched for predicted binding sites of Myc-regulated miRNAs, primarily those comprising the Myc-activated miR-17~92 cluster. Notably, gene set enrichment analysis (GSEA) demonstrates that miR-17~92 is a major regulator of B-cell receptor (BCR) pathway components. Many of them are immunoreceptor tyrosine inhibitory motif (ITIM)-containing proteins, and ITIM proteins CD22 and FCGR2B were found to be direct targets of miR-17~92. Consistent with the propensity of ITIM proteins to recruit phosphatases, either MYC or miR-17~92 expression was necessary to sustain phosphorylation of SYK and BLNK upon ligation of the BCR. Further downstream, stimulation of the BCR response by miR-17-92 resulted in the enhanced calcium flux and elevated levels of Myc itself. Notably, inhibition of the miR-17~92 cluster in diffuse large B-cell lymphoma (DLBCL) cell lines diminished the BCR response as measured by SYK and BLNK phosphorylation. Conversely, human DLBCLs of the BCR subtype express higher Myc and mir17hg transcript levels than other subtypes. Hence, the Myc-miR-17-92-BCR axis, frequently affected by genomic rearrangements, constitutes a novel lymphomagenic feed-forward loop

CBMi's Pichai Raman contributed to this article published online in Blood October 29, 2013.

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