Similar to resting mature B cells, where the B-cell antigen receptor (BCR) controls cellular survival1,2,3, 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 survival4,5,6,7. 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 (GSK3β) activity to support MYC-controlled gene expression. BCR− tumour cells exhibit increased GSK3β activity and are rescued from their competitive growth disadvantage by GSK3β inhibition. BCR− lymphoma variants that restore competitive fitness normalize GSK3β 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.
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Gene Expression Omnibus
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We thank members of the Casola laboratory, A. Ciliberto, K. L. Otipoby and R. Küppers for discussions; A. Ciliberto and N. Bolli for reading the manuscript; D. Wang, M. Caganova, L. Duarte and S. Ronzoni for preliminary work and technical assistance; F. D’Adda di Fagagna for reagents. We acknowledge the German International Cancer Genome Consortium (ICGC) Molecular Mechanisms in Malignant Lymphoma by Sequencing (MMML-Seq) and Molecular Mechanisms in Malignant Lymphoma (MMML) networks. This work was supported by the Italian Association for Cancer Research, the Giovanni Armenise/Harvard Foundation (to S.C.), the National Institutes of Health (to K.R.) and the European Research Council (to S.C. through FIRB IDEAS, and to K.R., Advanced Grant 268921). R.S. was supported by ICGC MMML-Seq grant 01KU1002, ICGC-DE-Mining grant 01KU1505G and e:BIO MMML-MYC-SYS grant 036166, as well as by the KinderKrebsInitiative Buchholz/Holm-Seppensen. G.V. and V.P were supported by the U. Veronesi Foundation. S.L. and M.B. were supported by Fondazione Beretta.
Extended data figures
This file contains Supplementary Tables 1-12.
About this article
Laboratory Investigation (2019)