| First Author | Sandhu SK | Year | 2013 |
| Journal | Proc Natl Acad Sci U S A | Volume | 110 |
| Issue | 45 | Pages | 18208-13 |
| PubMed ID | 24145403 | Mgi Jnum | J:202920 |
| Mgi Id | MGI:5523376 | Doi | 10.1073/pnas.1315365110 |
| Citation | Sandhu SK, et al. (2013) B-cell malignancies in microRNA Emu-miR-17~92 transgenic mice. Proc Natl Acad Sci U S A 110(45):18208-13 |
| abstractText | miR-17 approximately 92 is a polycistronic microRNA (miR) cluster (consisting of miR-17, miR-18a, miR-19a, miR-19b, miR-20a, and miR-92a) which frequently is overexpressed in several solid and lymphoid malignancies. Loss- and gain-of-function studies have revealed the role of miR-17 approximately 92 in heart, lung, and B-cell development and in Myc-induced B-cell lymphomas, respectively. Recent studies indicate that overexpression of this locus leads to lymphoproliferation, but no experimental proof that dysregulation of this cluster causes B-cell lymphomas or leukemias is available. To determine whether miR-17 approximately 92- overexpression induces lymphomagenesis/leukemogenesis, we generated a B-cell-specific transgenic mouse model with targeted overexpression of this cluster in B cells. The miR-17 approximately 92 overexpression was driven by the Emicro-enhancer and Ig heavy-chain promoter, and a 3' GFP tag was added to the transgene to track the miR expression. Expression analysis using Northern Blot and quantitative RT-PCR confirmed 2.5- to 25-fold overexpression of all six miRs in the transgenic mice spleens as compared with spleens from wild-type mice. Emicro-miR-17 approximately 92 mice developed B-cell malignancy by the age of 12-18 mo with a penetrance of approximately 80% (49% splenic B-cell lymphoproliferative disease, 28% lymphoma). At this stage mice exhibited severe splenomegaly with abnormal B-cell-derived white pulp expansion and enlarged lymph nodes. Interestingly, we found three classes of B-cell lymphomas/leukemias at varying grades of differentiation. These included expansion of CD19(+) and CD5(+) double-positive B cells similar to the aggressive form of human B-cell chronic lymphocytic leukemia, B220(+) CD43(+) B1-cell proliferation, and a CD19(+) aggressive diffuse large B-cell lymphoma-like disease, as assessed by flow cytometry and histopathological analysis. |
