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

• Published in: Leukemia Vol. 31; no. 11; pp. 2515 - 2522
• Main Authors: Germini, D, Tsfasman, T, Klibi, M, El-Amine, R, Pichugin, A, Iarovaia, O V, Bilhou-Nabera, C, Subra, F, Bou Saada, Y, Sukhanova, A, Boutboul, D, Raphaël, M, Wiels, J, Razin, S V, Bury-Moné, S, Oksenhendler, E, Lipinski, M, Vassetzky, Y S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2017; Nature Publishing Group
• Subjects: 13; 13/51; 14; 14/19; 14/32; 38/71; 38/77; 631/337/572; 631/45/612/1256; 631/67/1990/291/1621/1915; 631/80; 692/699/255/1901; 692/699/67/68/2486; Aged; Antiretroviral agents; Antiretroviral drugs; Antiretroviral therapy; B cells; B-Lymphocytes - metabolism; Blood circulation; Burkitt Lymphoma - genetics; Burkitt's lymphoma; Cancer Research; Chromosome translocations; Complications and side effects; Critical Care Medicine; Deoxyribonucleic acid; Development and progression; DNA; DNA damage; Female; Gene Products, tat - physiology; Genes, myc; Genetic aspects; Health risks; Heavy chains; Hematology; Highly active antiretroviral therapy; HIV; HIV (Viruses); Human immunodeficiency virus; Humans; Immunoglobulin Heavy Chains - genetics; Immunoglobulins; Intensive; Internal Medicine; Lymph nodes; Lymphocytes B; Lymphoma; Male; Medicine; Medicine & Public Health; Middle Aged; Myc protein; Non-Hodgkin's lymphoma; Non-Hodgkin's lymphomas; Nuclease; Nuclei; Nuclei (cytology); Oncology; original-article; Peripheral blood; Physiological aspects; RAG1 protein; Risk; Risk factors; Risk groups; Tat protein; Transcription; Translocation; France; Russia
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2017.106

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.