Synergy between PI3K Signaling and MYC in Burkitt Lymphomagenesis

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 con...

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Bibliographic Details
Published in:Cancer cell 2012-08, Vol.22 (2), p.167-179
Main Authors: Sander, Sandrine, Calado, Dinis P., Srinivasan, Lakshmi, Köchert, Karl, Zhang, Baochun, Rosolowski, Maciej, Rodig, Scott J., Holzmann, Karlheinz, Stilgenbauer, Stephan, Siebert, Reiner, Bullinger, Lars, Rajewsky, Klaus
Format: Article
Language:English
Subjects:
Animals
B-Lymphocytes - enzymology
B-Lymphocytes - pathology
Base Sequence
Burkitt Lymphoma - enzymology
Burkitt Lymphoma - genetics
Burkitt Lymphoma - pathology
Cell Line, Tumor
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - metabolism
Cell Transformation, Neoplastic - pathology
Enzyme Activation
Gene Expression Regulation, Neoplastic
Germinal Center - enzymology
Germinal Center - pathology
Humans
Mice
Mice, Inbred C57BL
Molecular Sequence Data
Phosphatidylinositol 3-Kinases - genetics
Phosphatidylinositol 3-Kinases - metabolism
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - metabolism
Signal Transduction - genetics
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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. ► Concomitant c-MYC and PI3K activation in germinal center B cells results in murine BL ► Several tertiary genetic alterations in the mouse are recurrent in human BL ► A preclinical model for studying BL biology and testing therapeutic options
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2012.06.012