Multicellular life requires altruistic cooperation between cells. The adaptive immune system is a notable exception, wherein germinal center B cells compete vigorously for limiting positive selection signals. Studying primary human lymphomas and developing new mouse models, we found that mutations affecting BTG1 disrupt a critical immune gatekeeper mechanism that strictly limits B cell fitness during antibody affinity maturation. This mechanism converted germinal center B cells into supercompetitors that rapidly outstrip their normal counterparts. This effect was conferred by a small shift in MYC protein induction kinetics but resulted in aggressive invasive lymphomas, which in humans are linked to dire clinical outcomes. Our findings reveal a delicate evolutionary trade-off between natural selection of B cells to provide immunity and potentially dangerous features that recall the more competitive nature of unicellular organisms.
Author Info: (1) Division of Hematology and Oncology, Department of Medicine and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (2) Division of Hematology and Oncology, Departm

Author Info: (1) Division of Hematology and Oncology, Department of Medicine and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (2) Division of Hematology and Oncology, Department of Medicine and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (3) Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY, USA. (4) Division of Hematology and Oncology, Department of Medicine and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA. Tri-Institutional PhD Program in Computational Biomedicine, New York, NY, USA. Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA. (5) Division of Hematology and Oncology, Department of Medicine and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (6) Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology (BRICS), Helmholtz Centre for Infection Research, Braunschweig, Germany. (7) Division of Hematology and Oncology, Department of Medicine and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (8) Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. (9) Department of Pathology, Yale School of Medicine, New Haven, CT, USA. (10) Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA. (11) Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY, USA. (12) Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology (BRICS), Helmholtz Centre for Infection Research, Braunschweig, Germany. (13) Department of Pharmacology and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (14) Department of Pharmacology and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (15) Molecular Pharmacology Program and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, and Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. (16) Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. (17) Division of Biostatistics, Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA. (18) Division of Hematology and Oncology, Department of Medicine and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (19) Division of Hematology and Oncology, Department of Medicine and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (20) Division of Hematology and Oncology, Department of Medicine and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (21) Division of Hematology and Oncology, Department of Medicine and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (22) Division of Hematology and Oncology, Department of Medicine and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA. (23) Department of Laboratory Medicine, University of California, San Francisco, CA, USA. (24) Division of Hematology and Oncology, Department of Medicine and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Weill Cornell Medicine-Qatar, Doha, Qatar. (25) Division of Hematology and Oncology, Department of Medicine and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (26) Division of Hematology and Oncology, Department of Medicine and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (27) Molecular Pharmacology Program and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, and Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK. (28) Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA. Caryl and Israel Englander Institute for Precision Medicine and Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA. (29) Molecular Pharmacology Program and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, and Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (30) Department of Pharmacology and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (31) Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. (32) Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA. Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA. (33) Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology (BRICS), Helmholtz Centre for Infection Research, Braunschweig, Germany. Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universitt Braunschweig, Braunschweig, Germany. (34) Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY, USA. (35) Division of Hematology and Oncology, Department of Medicine and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
