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Nature. 2017 Jun 8;546(7657):302-306. doi: 10.1038/nature22353. Epub 2017 May 31.

The B-cell receptor controls fitness of MYC-driven lymphoma cells via GSK3β inhibition.

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IFOM, the FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
Heidelberg Institute for Stem Cell Technology and Experimental Medicine, 69120 Heidelberg, Germany.
Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia, Spedali Civili, 25123 Brescia, Italy.
Max-Delbrück-Center of Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany.
Institute of Human Genetics, Christian-Albrechts-University Kiel, 24105 Kiel, Germany.
Department of Systems Biology and Department of Biomedical Informatics, Columbia University, New York, New York 10027, USA.
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy.
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.
Institute of Human Genetics, University Hospital of Ulm, 89081 Ulm, Germany.
Ateneo Vita Salute and San Raffaele Scientific Institute, Pathology and Lymphoid Malignancies Units, 20132 Milan, Italy.


Similar to resting mature B cells, where the B-cell antigen receptor (BCR) controls cellular survival, 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 survival. Consequently, the BCR signalling machinery has become an established target in the therapy of B-cell malignancies. 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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