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  • Original Article
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Transcriptional control and signal transduction, cell cycle

HIV Tat induces a prolonged MYC relocalization next to IGH in circulating B-cells

Leukemia volume 31, pages 2515–2522 (2017)Cite this article

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Abstract

With combined antiretroviral therapy (cART), the risk for HIV-infected individuals to develop a non-Hodgkin lymphoma is diminished. However, the incidence of Burkitt lymphoma (BL) remains strikingly elevated. Most BL present a t(8;14) chromosomal translocation which must take place at a time of spatial proximity between the translocation partners. The two partner genes, MYC and IGH, were found colocalized only very rarely in the nuclei of normal peripheral blood B-cells examined using 3D-FISH while circulating B-cells from HIV-infected individuals whose exhibited consistently elevated levels of MYC-IGH colocalization. In vitro, incubating normal B-cells from healthy donors with a transcriptionally active form of the HIV-encoded Tat protein rapidly activated transcription of the nuclease-encoding RAG1 gene. This created DNA damage, including in the MYC gene locus which then moved towards the center of the nucleus where it sustainably colocalized with IGH up to 10-fold more frequently than in controls. In vivo, this could be sufficient to account for the elevated risk of BL-specific chromosomal translocations which would occur following DNA double strand breaks triggered by AID in secondary lymph nodes at the final stage of immunoglobulin gene maturation. New therapeutic attitudes can be envisioned to prevent BL in this high risk group.

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Acknowledgements

We thank the National Institutes of Health AIDS Research and Reference Reagent Program for supplying critical reagents. This work was supported by grants from the ANRS to YV and TT; INSERM (ENVIBURKITT) to YV; the Russian Science Foundation #14-24-00022 to SR and OI and #14-15-00199 to YV.

Author contributions

ML, YV conceived and designed the study. DG, TT, MK, AP and REA designed and performed 3D-FISH experiments. DG and TT acquired and analyzed microscopic images, and interpreted the data. FS and SBM conceived HIV-1 experiments and analyzed the data. REA and YBS performed DNA damage experiments. AS analyzed the gene and protein expression data. DB and EO provided patients clinical data and samples. CBN performed cytogenetic analyses. MR, OI and SR critically interpreted the data. ML, DG, TT, EO, JW and YV wrote the manuscript.

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Author notes

  1. D Germini and T Tsfasman: These two authors contributed equally to this work.

Authors and Affiliations

  1. UMR 8126, Université Paris-Sud Paris-Saclay, CNRS, Institut Gustave Roussy, Villejuif, France

    D Germini, T Tsfasman, M Klibi, R El-Amine, A Pichugin, O V Iarovaia, C Bilhou-Nabera, Y Bou Saada, A Sukhanova, M Raphaël, J Wiels, M Lipinski & Y S Vassetzky

  2. LIA 1066, French-Russian Joint Cancer Research Laboratory, Villejuif, France

    D Germini, T Tsfasman, M Klibi, R El-Amine, A Pichugin, O V Iarovaia, C Bilhou-Nabera, Y Bou Saada, A Sukhanova, M Raphaël, J Wiels, S V Razin, M Lipinski & Y S Vassetzky

  3. Department of Biophysics, Institute of Physics, Nanotechnology, and Telecommunications, Peter the Great St. Petersburg Polytechnic University, St. Petersburg, Russia

    D Germini & A Pichugin

  4. Mechnikov Institute for Vaccines and Sera, Moscow, Russia

    T Tsfasman

  5. Institute of Gene Biology of the Russian Academy of Sciences, Moscow, Russia

    O V Iarovaia & S V Razin

  6. UMR8113, ENS de Cachan, Université Paris-Saclay, CNRS, Cachan, France

    F Subra & S Bury-Moné

  7. Department of Clinical Immunology, Hôpital Saint-Louis, Paris, France

    D Boutboul & E Oksenhendler

  8. EA3518, Université Paris Diderot, Paris, France

    D Boutboul & E Oksenhendler

  9. Lomonosov Moscow State University, Moscow, Russia

    S V Razin & Y S Vassetzky

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  1. D Germini
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Correspondence to M Lipinski or Y S Vassetzky.

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Germini, D., Tsfasman, T., Klibi, M. et al. HIV Tat induces a prolonged MYC relocalization next to IGH in circulating B-cells. Leukemia 31, 2515–2522 (2017). https://doi.org/10.1038/leu.2017.106

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