Integrated RNA-Seq-Mirnome Analysis Reveal Interplay of Multiple Cancer Signaling Pathways Involved in B Lymphomagenesis

Abstract 1294

Conditional inactivation of both the essential non-homologous DNA end-joining repair gene XRCC4 and the tumor suppressor gene p53 in mature B cells in mice frequently leads to mature B cell lymphomas. The majority of B lymphomas recurrently harbor reciprocal IgH/c-Myc translocations, activating c-Myc, a hallmark characteristic of Burkitt's lymphoma. We designed an integrated tumor RNA-Seq transcriptome profiling and miRnome based approach to dissect the interplay of signaling pathways and oncogenic signatures that lead to the development of the tumors in our model. Differential expression analysis of mRNA and 709 miRNAs reveal specific alterations in distinct signaling pathways, including upregulation of both Wnt and PI3K pathway signaling. For example, we found that Wnt10b, the wnt ligand expressed in B cells is upregulated. Correspondingly, frizzled receptors and it's downstream effector disheveled are also upregulated, factors that contribute to beta-catenin stabilization. Our studies also reveal increased expression PIK3CD, a PI3K catalytic isoform expressed in B cells, with corresponding downregulation of miRNAs with seed matches to 3'UTR of PIK3CD in the tumor; a factor that likely contribute to the stabilization of PIK3CD mRNA. Our analyses reveal an interplay of multiple pathway proteins and genes that serve as novel therapeutic targets for human B lymphoma.