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

B-cell receptor (BCR) signaling is critically activated and stable for mantle cell lymphoma (MCL), but 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. We 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. To comprehensively identify miR-17-92 cluster target genes, we performed pulldown-seq, where target RNA of miRNA was captured using the biotinylated miRNA mimics and magnetic bead-coated streptavidin, and quantified using next-generation sequencing. The pulldown-seq identified novel miRNA target genes, including tumor suppressors such as BTG2 (miR-19b), CDKN2A (miR-17), SYNE1 (miR-20a), TET2 (miR-18, miR-19b, and miR-92a), TNFRSF10A (miR-92a), and TRAF3 (miR-17). Notably, the gene expression profile data of patients with MCL revealed that BTG2 expression was negatively associated with that of BCR signature genes, and low BTG2 expression was associated with poor overall survival. Moreover, BTG2 silencing in MCL cell lines significantly induced BCR signaling overactivation and cell proliferation. Our results suggest an oncogenic role of miR-17-92 cluster-activating BCR signaling throughout BTG2 deregulation in MCL. Furthermore, this may contribute to the prediction of the therapeutic efficacy and improved outcomes of MCL. SOX11 and enhancer-regulated mechanism induce overexpression of miR-17-92 in mantle cell lymphoma (MCL). BTG2 was identified as a novel target of miR-17-92 cluster. miR-17-92 cluster activates B-cell receptor signaling and cell proliferation by regulating BTG2 in MCL.image

Automated summary

The miR-17-92 cluster activates the BCR signaling pathway in MCL by regulating BTG2, resulting in cell proliferation. Silencing BTG2 leads to overactivation of the BCR signaling pathway and cell proliferation. These findings contribute to predicting therapeutic efficacy and improving outcomes in MCL.