title: B-cell malignancies in microRNA Eμ-miR-17~92 transgenic mice.
abstract: miR-17∼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∼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∼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∼92 overexpression was driven by the Eµ-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. Eµ-miR-17∼92 mice developed B-cell malignancy by the age of 12-18 mo with a penetrance of ∼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.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210.
authors.forename: Sukhinder K
authors.initials: SK
authors.lastname: Sandhu
authors.forename: Matteo
authors.initials: M
authors.lastname: Fassan
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: Francesca
authors.initials: F
authors.lastname: Lovat
authors.forename: Veronica
authors.initials: V
authors.lastname: Balatti
authors.forename: Yuri
authors.initials: Y
authors.lastname: Pekarsky
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006652:Histological Techniques; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013154:Spleen / Q000378:metabolism
chemical_list: C575895:MIRN17-92 microRNA, mouse; D035683:MicroRNAs
keywords: SLC/ABC transporters; animal model; miR-17∼92 cluster