Abstract 2947: B-cell lymphoma in eα-miR-17∼92 transgenic mice (2012)

Abstract The miR-17∼92 is a polycistronic miRNA cluster, consisting of six miRNAs: miR-17, miR-18a, miR-19a, miR-19b, miR-20a and miR-92a encoded from last exon of a non-coding RNA. It is frequently overexpressed in variety of solid and lymphoid malignancies and has been appropriately called Oncomir-1. Loss-of-function studies revealed a role of miR-17∼92 in heart and lung development, and gain-of-function studies have shown its role in myc induced B-cell lymphomas. In addition to its role in tumorigenesis, the cluster is involved in regulation of lymphocyte development. Some of the key targets of this miRNA include the tumor suppressor, Pten and the proapoptotic, Bim gene. In order to study the mechanisms by which miR-17∼92 overexpression induce tumorigenesis, we generated a B-cell specific transgenic mouse model. The miR-17∼92 overexpression was driven by the eμ enhancer and immunoglobulin heavy chain promoter with a 3′ Green Fluorescent Protein (GFP) tag in order to track the miRNA expression. Expression analysis using Northern Blot and qRT-PCR yielded four founders with significant overexpression of all six miRNAs in their spleens. Quantitative RT-PCR analysis showed significant overexpression of all six miRNAs ranging from 2.5 to 25-fold in spleen cells. Flow cytometry analysis of spleens from 9-month old healthy transgenic mice showed significantly increased CD43+TCR- population as compared to wild type mice. In older mice (18-months) the symptoms are more pronounced with mice developing ascites, enlarged spleen and lymph nodes. The flow analysis of spleens from these mice showed CD19+CD5+ B-cell population similar to human chronic lymphocytic leukemia (CLL). Histological analysis showed multiple organs (lungs, kidney, brain) infiltrated by these lymphoma cells. Southern Blot analysis showed these cells to be oligoclonal B cells, while no T cell clonality was observed. Total mRNA profiling from these malignant cells showed that 782 genes are up- and 1019 genes are down-regulated in transgenic B-cells versus wild type CD19+ B-cells. Ingenuity pathway analysis showed majority of the downregulated genes are represented by Hematological System Development and Function, and Inflammatory Response pathways, while the upregulated genes are represented by cell cycle pathway. Some of the upregulated genes in miR-17∼92 over-expressing malignant B-cells as compared to normal CD19+ B-cells included ZAP-70, CCL5, NONO, previously reported in B-CLL gene signature. Among other overexpressed genes, cJun, cFos and ATF3, were upregulated 5-fold, 67-fold and 18-fold, respectively. We hypothesize that AP-1 dependent transcription may be one of the key survival factors in the miR-17∼92 driven lymphomas. Currently, we are exploring the negative regulators of the oncogenic cJun signaling pathway which may be miR-17∼92 targets. Overall, we found that miR-17∼92 overexpression in mice has the ability to induce B-cell lymphoma which can develop into CLL at an older age. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2947. doi:1538-7445.AM2012-2947