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MYC directly transactivates CR2/CD21, the receptor of the Epstein–Barr virus, enhancing the viral infection of Burkitt lymphoma cells

Oncogene volume 42, pages 3358–3370 (2023)Cite this article

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Abstract

MYC is an oncogenic transcription factor dysregulated in about half of total human tumors. While transcriptomic studies reveal more than 1000 genes regulated by MYC, a much smaller fraction of genes is directly transactivated by MYC. Virtually all Burkitt lymphoma (BL) carry chromosomal translocations involving MYC oncogene. Most endemic BL and a fraction of sporadic BL are associated with Epstein–Barr virus (EBV) infection. The currently accepted mechanism is that EBV is the BL-causing agent inducing MYC translocation. Herein we show that the EBV receptor, CR2 (also called CD21), is a direct MYC target gene. This is based on several pieces of evidence: MYC induces CR2 expression in both proliferating and arrested cells and in the absence of protein synthesis, binds the CR2 promoter and transactivates CR2 in an E-box-dependent manner. Moreover, using mice with conditional MYC ablation we show that MYC induces CR2 in primary B cells. Importantly, modulation of MYC levels directly correlates with EBV’s ability of infection in BL cells. Altogether, in contrast to the widely accepted hypothesis for the correlation between EBV and BL, we propose an alternative hypothesis in which MYC dysregulation could be the first event leading to the subsequent EBV infection.

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Fig. 1: Downregulation of MYC results in lower CR2 expression.
Fig. 2: MYC induces CR2 expression in arrested cells.
Fig. 3: Binding of MYC to the promoter of CR2.
Fig. 4: CR2 is a direct MYC target gene.
Fig. 5: Myc induces CR2 expression in primary B cells.
Fig. 6: MYC depletion decreases EBV infection of B cells.
Fig. 7: MYC overexpression increases EBV infection of B cells.
Fig. 8: Two non-mutually exclusive models for pathogenesis of Burkitt lymphoma.

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The authors declare that all data that support the findings of this study are available within the paper and supplementary files.

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Acknowledgements

The work was supported by grants PID2020-115903GB-100 to JL and MDD, RTI2018-095673-B-I00 to JRR, PID2019-107551RB-I00 to VG-Y, PID2020-119567RB-I00 to RM, PID2020-117539GB-I00 to IV and PID2019-106773RB-I00 to ARR, all funded by MCIN/AEI/10.13039/501100011033/, Spanish Government, and by “FEDER, Una manera de hacer Europa”, European Union, and by La Caixa HR17-0244 grant to AR. LQ and VJ were recipients of F.P.U. program and Universidad de Cantabria fellowships, respectively. LG-G was a fellow of the Maria Zambrano program, Spanish Government. We are grateful to Maria Aramburu and Patricia Arribas for technical help, Santiago Montes for useful comments and Victor Campa por assistance in microscopy and image processing.

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  1. Ester Molina

    Present address: The Hormel Institute, University of Minnesota, Austin, MN, USA

  2. These authors contributed equally: Ester Molina, Lucía García-Gutiérrez.

Authors and Affiliations

  1. Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Universidad de Cantabria-CSIC, Santander, Spain

    Ester Molina, Lucía García-Gutiérrez, Vanessa Junco, Rosa Blanco, Laura Quevedo, Juan C. Acosta, Ramon Merino, M. Dolores Delgado, Ignacio Varela & Javier León

  2. Departamento de Biología Molecular, Universidad de Cantabria, Santander, Spain

    Ester Molina, Lucía García-Gutiérrez, Vanessa Junco, Rosa Blanco, Laura Quevedo, Juan C. Acosta, Ramon Merino, M. Dolores Delgado, Ignacio Varela & Javier León

  3. Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB)-CSIC, Madrid, Spain

    Mercedes Perez-Olivares & Ignacio Moreno de Alborán

  4. Centro Nacional de Investigaciones Cardiovasculares-CNIC Carlos III, Madrid, Spain

    Virginia G. de Yébenes & Almudena R. Ramiro

  5. Department of Immunology, Ophthalmology and ENT, Universidad Complutense, School of Medicine and 12 de Octubre Health Research Institute (imas12), Madrid, Spain

    Virginia G. de Yébenes, Ana V. Marín & José R. Regueiro

  6. School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia

    Daniela Ulgiati

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Contributions

EM, LG-G: formal analysis, investigation, writing. VJ, MP-O, VG-Y, RB, AVM, JCA and LQ: formal analysis, investigation, resources. DU, RM, JRR, and IV: formal analysis and resources. IMA, AR: formal analysis, resources, editing. MDD: formal analysis, funding. JL: experimental design, formal analysis, writing, funding acquisition.

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Molina, E., García-Gutiérrez, L., Junco, V. et al. MYC directly transactivates CR2/CD21, the receptor of the Epstein–Barr virus, enhancing the viral infection of Burkitt lymphoma cells. Oncogene 42, 3358–3370 (2023). https://doi.org/10.1038/s41388-023-02846-9

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