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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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.

Author information

Author notes

    • Gabriele Varano
    •  & Simon Raffel

    These authors contributed equally to this work.


  1. IFOM, the FIRC Institute of Molecular Oncology, 20139 Milan, Italy

    • Gabriele Varano
    • , Martina Sormani
    • , Federica Zanardi
    • , Laura Perucho
    • , Valentina Petrocelli
    •  & Stefano Casola
  2. Heidelberg Institute for Stem Cell Technology and Experimental Medicine, 69120 Heidelberg, Germany

    • Simon Raffel
  3. Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia, Spedali Civili, 25123 Brescia, Italy

    • Silvia Lonardi
    • , Mattia Bugatti
    •  & Fabio Facchetti
  4. Max-Delbrück-Center of Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany

    • Christin Zasada
    • , Stefan Kempa
    •  & Klaus Rajewsky
  5. Institute of Human Genetics, Christian-Albrechts-University Kiel, 24105 Kiel, Germany

    • Andrea Haake
    • , Ulrike Paul
    •  & Reiner Siebert
  6. Department of Systems Biology and Department of Biomedical Informatics, Columbia University, New York, New York 10027, USA

    • Albert K. Lee
    •  & Raul Rabadan
  7. Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy

    • Eelco Van Anken
  8. Institute for Cancer Genetics and the Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA

    • Laura Pasqualucci
  9. Institute of Human Genetics, University Hospital of Ulm, 89081 Ulm, Germany

    • Reiner Siebert
  10. Ateneo Vita Salute and San Raffaele Scientific Institute, Pathology and Lymphoid Malignancies Units, 20132 Milan, Italy

    • Maurilio Ponzoni


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M.S. and F.Z. contributed equally to this work. G.V. performed most experiments. S.R. made initial observations. M.S. performed CAL-101 lymphoma sensitivity assays, in vivo transplantations and biochemical analyses. M.S. analysed Xbp1 expression with E.V.A. F.Z. performed BCR complementation studies and bioinformatics analyses on transcriptome and exome sequencing data. C.Z. and M.S. performed metabolic labelling of lymphomas. C.Z. and S.K. analysed and interpreted metabolomic data. L.Pe. investigated the role of cell contact and soluble factors in the counter-selection of BCR tumour cells. V.P. performed Burkitt lymphoma immunoglobulin gene rearrangement analyses and Ras complementation assays. S.L., M.B., M.P. and F.F. performed immunohistochemical analyses and interpreted the results. A.H., U.P. and R.S. analysed RAS genes in Burkitt lymphoma. A.K.L., L.Pa. and R.R. assisted with exome sequencing analyses. S.C. and K.R. conceived the project. S.C. designed the experiments and interpreted the results with G.V. S.C. wrote and edited the manuscript with help from K.R. and G.V.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Stefano Casola.

Reviewer Information Nature thanks J. Burger, A. Schaffer and A. Thomas-Tikhonenko for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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