miR-17-92 cluster-BTG2 axis regulates B-cell receptor signaling in mantle cell lymphoma

Abstract

Abstract B-cell receptor (BCR) signaling is critically activated and targetable for mantle cell lymphoma (MCL); however, the underlying mechanism of the activated BCR signaling pathway is not clear. The pathogenic basis of miR-17-92 cluster remains unclear although the oncogenic microRNA (miRNA) miR-17-92 cluster is highly expressed in patients with MCL. This study revealed that miR-17-92 cluster overexpression is partly dependent on SOX11 expression and chromatin acetylation of MIR17HG enhancer regions. Moreover, miR-17-92 cluster regulates not only cell proliferation but BCR signaling activation in MCL cell lines. Pulldown-seq, where mRNA was captured using biotinylated miRNA transfection, was performed and analyzed with next-generation sequencing. Additionally, novel miRNA targets, including tumor suppressors such as BTG2, were identified to comprehensively define miR-17-92 cluster targets. Notably, gene expression profile data of patients with MCL revealed that BTG2 expression was negatively associated with those of BCR signature genes. Moreover, BTG2 silencing in MCL cell lines significantly induced BCR signaling overactivation. Our results suggest an oncogenic role of miR-17-92 cluster-activating BCR signaling throughout BTG2 deregulation in MCL.