The B-cell receptor controls fitness of MYC-driven lymphoma cells via GSK3ß inhibition

G Varano, S Raffel, M Sormani, Federica Zanardi, S Lonardi, C Zasada, L Perucho, V Petrocelli, A Haake, AK Lee, Mattia Bugatti, U Paul, E Van Anken, L Pasqualucci, R Rabadan, R Siebert, S Kempa, M Ponzoni, F Facchetti, K RajewskyS Casola

Research output: Contribution to journalArticle

Abstract

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. © 2017 Macmillan Publishers Limited, part of Springer Nature.
Original languageEnglish
Pages (from-to)302-306
Number of pages5
JournalNature
Volume546
Issue number7657
DOIs
Publication statusPublished - 2017

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    Varano, G., Raffel, S., Sormani, M., Zanardi, F., Lonardi, S., Zasada, C., Perucho, L., Petrocelli, V., Haake, A., Lee, AK., Bugatti, M., Paul, U., Van Anken, E., Pasqualucci, L., Rabadan, R., Siebert, R., Kempa, S., Ponzoni, M., Facchetti, F., ... Casola, S. (2017). The B-cell receptor controls fitness of MYC-driven lymphoma cells via GSK3ß inhibition. Nature, 546(7657), 302-306. https://doi.org/10.1038/nature22353