Abstract IA21: The MYC-microRNA pathway in B-cell neoplasms

Abstract

Abstract MYC is a noncanonical transcription factor that binds to thousands of genomic loci and affects over 15% of the human transcriptome, with surprisingly little overlap between MYC-bound and MYC-regulated genes. This discordance raises the question whether MYC chooses its targets based on their individual biological effects (“a la carte”) or by virtue of belonging to a certain group of genes (on a “prix fixe” basis). Over the last few years, we have developed a model wherein MYC initially deregulates a select number of microRNAs. These microRNAs then target a broad spectrum of genes based solely on the presence in their 3' UTRs (untranslated regions) of distinct “seed” sequences. Existing evidence suggests that there are significant microRNA components to all key MYC-driven phenotypes, including cell-cycle progression, apoptosis, metabolism, angiogenesis, metastasis, stemness, and last but not least – hematopoiesis (1). For example in a human B-lymphoid cell line, Myc-repressed 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 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 is necessary to sustain phosphorylation of spleen tyrosine kinase (SYK) and the B-cell linker protein (BLNK) upon ligation of the BCR. Further downstream, stimulation of the BCR response by miR-17-92 resulted in the enhanced calcium flux, activation of the CD19-PI3K axis, and elevated levels of Myc itself (2). 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 (3).