Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in Eμ-miR155 transgenic mice

Abstract

MicroRNAs (miRNAs) represent a newly discovered class of posttranscriptional regulatory noncoding small RNAs that bind to targeted mRNAs and either block their translation or initiate their degradation. miRNA profiling of hematopoietic lineages in humans and mice showed that some miRNAs are differentially expressed during hematopoietic development, suggesting a role in hematopoietic cell differentiation. In addition, recent studies suggest the involvement of miRNAs in the initiation and progression of cancer. miR155 and BIC, its host gene, have been reported to accumulate in human B cell lymphomas, especially in diffuse large B cell lymphomas, Hodgkin lymphomas, and certain types of Burkitt lymphomas. Here, we show that E-mmu-miR155 transgenic mice exhibit initially a preleukemic pre-B cell proliferation evident in spleen and bone marrow, followed by frank B cell malignancy. These findings indicate that the role of miR155 is to induce polyclonal expansion, favoring the capture of secondary genetic changes for full transformation. Since their discovery in 1993 in Caenorhabditis elegans (1), there have been numerous reports that implicated these tiny molecules in the posttranscriptional regulation of a large array of proteins with very diverse roles, ranging from cell proliferation and differentiation to lipid metabolism (2-6).miRNA profiling of hematopoietic lineages in humans and mice showed that miRNAs are differentially expressed in the course of hematopoietic development, suggesting a potential role in hematopoietic differentiation (7-9). We have shown that miR-15a and miR-16-1 are deleted or down-regulated in Ϸ68% of cases of chronic lymphocytic leukemia (CLL) (10, 11), and that miRNAs genes are frequently located at fragile sites and other genomic regions involved in cancers (12). Transcripts of miR155 and BIC (its host gene) transcripts have been shown to accumulate in human B cell lymphomas, especially diffuse large B cell lymphomas (13), Hodgkin lymphomas (14), and subsets of Burkitt lymphomas (latency type III Epstein-Barr virus-positive Burkitt lymphoma; ref. 15). These reports provide indirect evidence that miR155 may play a role in B cell development and lymphomagenesis. We have also reported that miR155 is overexpressed in the aggressive form of CLL (11).Here, we show that the transgenic mice carrying a miR155 transgene whose expression is targeted to B cells (E-mmumiR155) exhibit initially a preleukemic pre-B cell proliferation, evident in spleen and bone marrow, and later develop a frank B cell malignancy. Results and DiscussionProduction and Characterization of E-mmu-miR155. We generated transgenic mice in which the expression of mmu-miR155 (mouse miR155) is under the control of a V H promoter-Ig heavy chain E enhancer, which becomes active at the late pro-B cell stage of the B cell development. Fifteen transgenic founders were identified by Southern blot hybridization, seven on C57BL͞B6 and eight on FVB͞N backgrounds. These were bred to wild-type mice of the same strain to produce 15 independent...

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