The B-cell receptor controls fitness of MYC-driven lymphoma cells via GSK3ß inhibition
| Autor: | Klaus Rajewsky, Fabio Facchetti, Simon Raffel, Maurilio Ponzoni, Andrea Haake, Silvia Lonardi, Laura Pasqualucci, Federica Zanardi, Stefan Kempa, Eelco van Anken, Gabriele Varano, Martina Sormani, Ulrike Paul, Laura Perucho, Mattia Bugatti, Christin Zasada, Reiner Siebert, Albert Lee, Stefano Casola, Valentina Petrocelli, Raul Rabadan |
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| Přispěvatelé: | Varano, G., Raffel, S., Sormani, M., Zanardi, F., Lonardi, S., Zasada, C., Perucho, L., Petrocelli, V., Haake, A., Lee, A. K., Bugatti, M., Paul, U., Van Anken, E., Pasqualucci, L., Rabadan, R., Siebert, R., Kempa, S., Ponzoni, M., Facchetti, F., Rajewsky, K., Casola, S., VAN ANKEN, Eelco |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Male Lymphoma Lymphoma B-cell-Receptor MYC Cell-competition Cell Genes myc medicine.disease_cause Mice 0302 clinical medicine hemic and lymphatic diseases Receptors Tumor Cells Cultured B-cell lymphoma ras Mutation B-Lymphocytes Cultured Multidisciplinary breakpoint cluster region myc Burkitt Lymphoma Tumor Cells Gene Expression Regulation Neoplastic medicine.anatomical_structure 030220 oncology & carcinogenesis Antigen Female MAP Kinase Signaling System B-cell receptor Receptors Antigen B-Cell Biology NO 03 medical and health sciences B-cell-Receptor medicine Animals Humans Carbon Genes ras Glycogen Synthase Kinase 3 beta Genetic Fitness Neoplastic Cell-competition B-Cell medicine.disease 030104 developmental biology Gene Expression Regulation Genes Cancer research Carcinogenesis |
| Popis: | Similar to resting mature B cells, where the B-cell antigen receptor (BCR) controls cellular survival1-3, surface BCR expression is conserved in most mature B-cell lymphomas. The identification of activating BCR mutations and the growth disadvantage upon BCR knockdown of cells of certain lymphoma entities has led to the view that BCR signalling is required for tumour cell survival4-7. Consequently, the BCR signalling machinery has become an established target in the therapy of B-cell malignancies8,9. Here we study the effects of BCR ablation on MYC-driven mouse B-cell lymphomas and compare them with observations in human Burkitt lymphoma. Whereas BCR ablation does not, per se, significantly affect lymphoma growth, BCR-negative (BCR-) tumour cells rapidly disappear in the presence of their BCR-expressing (BCR+) counterparts in vitro and in vivo. This requires neither cellular contact nor factors released by BCR+ tumour cells. Instead, BCR loss induces the rewiring of central carbon metabolism, increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuates glycogen synthase kinase 3 beta (GSK3ß) activity to support MYC-controlled gene expression. BCR- tumour cells exhibit increased GSK3ß activity and are rescued from their competitive growth disadvantage by GSK3ß inhibition. BCR- lymphoma variants that restore competitive fitness normalize GSK3ß activity after constitutive activation of the MAPK pathway, commonly through Ras mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate immunoglobulin-crippled tumour cells, which usually represent a minority of the tumour bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR-targeted therapies may profit from combinations with drugs targeting BCR- tumour cells. |
| Databáze: | OpenAIRE |
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