Abstract 1952: The rapid generation of mouse B cell lymphomas by lentiviral mediated overexpression of miR-1204 from a genetically unstable region of human 8q24

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Abstract SNPs in the area surrounding MYC on human 8q24 have recently been found by Genome Wide Association (GWA) to be associated with susceptibility to a number of malignancies including prostate, breast, colorectal and bladder carcinomas (CA). This genetically unstable region is also a frequent target of chromosomal translocation (Tx), amplification or retroviral integration in a number of CAs such as breast, prostate, ovarian, colon, pancreatic, and cervical. In one example, essentially 100% of patients with Burkitt's lymphoma exhibit one of three characteristic non-random chromosomal Txs that places MYC or the immediate surrounding region in close proximity to enhancers of the immunoglobulin (Ig) heavy chain or light chain loci. Although de-regulated MYC expression could be assumed to be the target of the genomic instability or GWA-based susceptibility, no clear correlation between MYC expression and disease has been established. A possible alternative target has been identified in a series of transcripts cloned from the PVT1 region downstream of MYC. However, the extent of alternative splicing coupled with the lack of a coding region has made it difficult to assign a specific role for any PVT1-derived transcripts. Recently, we have identified a cluster of small RNAs exhibiting the hairpin formation, sequence conservation and expression characteristics of miRNAs (miR-1204∼1208) within the transcriptional domain of PVT1. Increased expression of several of these miRNAs in tumors harboring amplified MYC/PVT1 or Burkitt lymphomas with the 8q24 Tx suggests a possible role for these miRNAs in tumorigenesis, especially for miR-1204 which is found 60 kb downstream of MYC, flanking exon 1b of PVT1. An increased expression of miR-1204 in pre-B cells compared to pro-B cells also suggested a lymphoid specific developmental pattern of expression. Lentiviral constructs of miR-1204 under control of a CMV promoter (LentiCMV-miR-1204) revealed a possible effect on MYC, but in a pre-B (not pro-B) specific environment. Introduction of LentiCMV-miR-1204 into mice harboring either a MYC (C.iMYC) or IL6 (C.IL6) transgene resulted in high frequency and rapid onset of large B cell lymphomas (∼16 or 82 days vs. 91 or 117 days for controls, respectively). While these results point to over-expression of miR-1204 playing a specific role in the development of B cell malignancy, additional studies with the LentiCMV-miR-1204 construct in other tumor cell lines (prostate and breast) also reveal phenotypic changes in cell proliferation and migration. Further studies using lentiviruses with alternative promoters for miR-1204 and the other 8q24 associated miRNAs are underway to identify downstream targets and pathways not only in lymphoid malignancy but also in the wide range of malignancies associated with GWA-susceptibility and genomic instability. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1952.