The role of the PTEN/PI3K pathway in the molecular pathogenesis of germinal center B-cell-like diffuse large B cell lymphoma
Final Report Abstract
Diffuse large B-cell lymphoma (DLBCL) represents the most common type of malignant lymphoma. It is considered as heterogeneous diagnostic category and by performing gene expression profiling different molecular subtypes can be distinguished. Despite recent advances in the understanding of the biology of these entities, many pathogenetic mechanisms remain unknown. In the funded project, we investigated the role of the oncogenic phosphatidylinositol- 3-kinase (PI3K)/AKT signaling pathway in germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL. Our analyses revealed that the molecular mechanisms leading to constitutive activation of PI3K/AKT are different in GCB and ABC DLBCL. In GCB DLBCLs the predominant mode of activation is loss of the tumor suppressor PTEN that acts as the physiological antagonist of PI3K/AKT. The majority of primary GCB DLBCLs are characterized by loss of PTEN. In contrast, only a minority of ABC DLBCLs have this abnormality. In GCB DLBCL, PTEN loss leads to constitutive activation of PI3K/AKT and to expression of the oncogenic transcription factor MYC. In contrast, in ABC DLBCL, chronic B- cell receptor signaling seems to be causative for PI3K/AKT signaling. Addiction to PI3K is caused by functional interaction with the nuclear factor-kappa B (NF-κB) pathway. In these PI3K-dependent ABC DLBCLs as well as in PTEN-deficient GCB DLBCLs, the PI3K/AKT pathway seems to represent a very promising therapeutic target for the treatment of affected patients.
Publications
- Critical role of PI3K signaling for NF-kappaB-dependent survival in a subset of activated B-cell-like diffuse large B-cell lymphoma cells. PNAS. 2011; 108 (1): 272-7
Kloo B., Nagel D., Pfeifer M., Grau M., Düwel M., Vincendeau M., Dörken B., Lenz P., Lenz G., Krappmann D.
- Malt1-dependent RelB cleavage promotes canonical NF-κB activation in lymphocytes and lymphoma cell lines. PNAS. 2011; 108 (35): 14596-601
. Hailfinger S., Nogai H., Pelzer C., Jaworski M., Cabalzar K., Charton JE., Guzzardi M., Decaillet C., Grau M., Dörken B., Lenz P., Lenz G., Thome M.
- Pathogenesis of non-Hodgkin’s lymphoma. Journal of Clinical Oncology. 2011; 29 (14): 1803-11
Nogai H., Dörken B., Lenz G.
- Protein kinase C inhibitor sotrastaurin selectively inhibits the growth of CD79 mutant diffuse large B- cell lymphomas. Cancer Research. 2011; 71 (7): 2643-53
Naylor TL., Tang H., Ratsch BA., Enns A., Loo A., Chen L., Lenz P., Waters NJ., Schuler W., Dörken B., Yao YM., Warmuth M., Lenz G., Stegmeier F.
- New insights into the biology of molecular subtypes of diffuse large B-cell lymphoma and Burkitt lymphoma. Best Practice and Research Clinical Haematology. 2012; 25 (1): 3-12
Frick M., Dörken B., Lenz G.
(See online at https://doi.org/10.1016/j.beha.2012.01.003) - PTEN loss defines a PI3K/AKT pathway-dependent germinal center subtype of diffuse large B-cell lymphoma. PNAS. 2013 [Epub ahead of print]
Pfeifer M., Grau M., Lenze D., Wenzel SS., Wolf A., Wollert-Wulf B., Dietze K., Nogai H., Storek B., Madle H., Dörken B., Janz M., Dirnhofer S., Lenz P., Hummel M., Tzankov A., Lenz G.
(See online at https://doi.org/10.1073/pnas.1305656110) - The protease activity of the paracaspase MALT1 is controlled by monoubiquitination. Nature Immunology. 2013; 14 (4): 337-45
Pelzer C., Cabalzar K., Wolf A., Gonzalez M., Lenz G., Thome M.
(See online at https://doi.org/10.1038/ni.2540)
