The genomic region encoding the miR-17−92 microRNA (miRNA) cluster is often amplified in lymphoma and other cancers, and miRNAs within this cluster are expressed in high amounts in cancer cells carrying this amplification. Retroviral expression of miR-17−92 accelerates cMyc-induced lymphoma development, but precisely how elevated miR-17−92 expression promotes lymphomagenesis remains unclear. Here we generated mice with elevated miR-17−92 expression in lymphocytes. These mice developed lymphoproliferative disease and autoimmunity, and died prematurely. Lymphocytes from these mice showed increased proliferation and reduced activationinduced cell death. miR-17−92 miRNAs suppressed expression of the tumor suppressor Pten and the pro-apoptotic protein Bim. This mechanism likely contributed to the lymphoproliferative disease and autoimmunity observed in miR-17−92 transgenic mice, and to lymphoma development in patients carrying amplifications of the miR-17−92 coding region.

Summary Previous work has shown that mature B cells depend upon survival signals delivered to the cells by their antigen receptor (BCR). To identify the molecular nature of this survival signal, we have developed a genetic approach in which ablation of the BCR is combined with the activation of specific, BCR dependent signaling cascades in mature B cells in vivo. Using this system, we provide evidence that the survival of BCR deficient mature B cells can be rescued by a single signaling pathway downstream of the BCR, namely PI3K signaling, with the FOXO1 transcription factor playing a central role.

SUMMARY In Burkitt lymphoma (BL), a germinal center B-cell-derived tumor, the pro-apoptotic properties of c-MYC must be counterbalanced. Predicting that survival signals would be delivered by phosphoinositide-3-kinase (PI3K), a major survival determinant in mature B cells, we indeed found that combining constitutive c-MYC expression and PI3K activity in germinal center B cells of the mouse led to BL-like tumors, which fully phenocopy human BL with regard to histology, surface and other markers, and gene expression profile. The tumors also accumulate tertiary mutational events, some of which are recurrent in the human disease. These results and our finding of recurrent PI3K pathway activation in human BL indicate that deregulated c-MYC and PI3K activity cooperate in BL pathogenesis.