Synergy between PI3K Signaling and MYC in Burkitt Lymphomagenesis

In Burkitt lymphoma (BL), an aggressive germinal-center (GC) derived non-Hodgkin B-cell lymphoma characterized by MYC translocations as early transforming event, the apoptotic properties of MYC must have been overcome by pro-survival signals. Whereas activation of the pro-survival factor NFkappaB is not eminent in BL, PI3K signalling, which mediates B cell receptor associated survival signals in mature B cells, might be the cooperating event. Here we prove this hypothesis by the generation of BL in mice upon concordant expression of MYC and activation of PI3K in GC B cells. Unlike existing murine BL-like models, our tumour model fully phenocopies primary human BL and reflects the complexity of the disease with regard to histological appearance, surface marker expression, and characteristic gene expression profiles. Like in human BL, tumour monoclonality indicated a multistep pathogenesis underlining MYC and PI3K as predisposing events that invariably lead to GC-derived BL formation. In accordance, copy number alteration analysis revealed genomic regions involved in BL pathogenesis.

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Sander S, Calado DP, Srinivasan L, Köchert K, Zhang B, Rosolowski M, Rodig SJ, Holzmann K, Stilgenbauer S, Siebert R, Bullinger L, Rajewsky K