Mouse model of endemic Burkitt translocations reveals the long-range boundaries of Ig-mediated oncogene deregulation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 27; pp. 10972 - 10977
• Main Authors: Kovalchuk, Alexander L, Ansarah-Sobrinho, Camilo, Hakim, Ofir, Resch, Wolfgang, Tolarová, Helena, Dubois, Wendy, Yamane, Arito, Takizawa, Makiko, Klein, Isaac, Hager, Gordon L, Morse, Herbert C, Potter, Michael, Nussenzweig, Michel C, Casellas, Rafael
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 03.07.2012; National Acad Sciences
• Subjects: Africans; animal models; Animals; B lymphocytes; B-Lymphocytes - cytology; B-Lymphocytes - physiology; Biological Sciences; Burkitt lymphoma; Burkitt Lymphoma - epidemiology; Burkitt Lymphoma - genetics; Cells, Cultured; children; Chromatin; chromosome translocation; Chromosomes; cytidine; Cytidine - genetics; Disease Models, Animal; Endemic Diseases; Enhancer Elements, Genetic - genetics; Epigenesis, Genetic - genetics; Epigenetics; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Gene Rearrangement, B-Lymphocyte - genetics; Genes, Immunoglobulin Heavy Chain - genetics; Genes, myc - genetics; Genetic loci; histones; Human herpesvirus 4; Humans; Immunoglobulin Class Switching - genetics; Lymphoma; lysine; malaria; Mice; neoplasm cells; Oncogene Proteins, Fusion - genetics; Oncogenes; Plasma cells; Plasma Cells - cytology; Plasma Cells - physiology; Plasmacytoma; precipitin tests; regulatory sequences; Rodents; transcription (genetics); Transcription Initiation Site - physiology; Translocation, Genetic - genetics; Tumors; uracil; Uracil-DNA Glycosidase - genetics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1200106109

Human Burkitt lymphomas are divided into two main clinical variants: the endemic form, affecting African children infected with malaria and the Epstein-Barr virus, and the sporadic form, distributed across the rest of the world. However, whereas sporadic translocations decapitate Myc from 5′ proximal regulatory elements, most endemic events occur hundreds of kilobases away from Myc . The origin of these rearrangements and how they deregulate oncogenes at such distances remain unclear. We here recapitulate endemic Burkitt lymphoma-like translocations in plasmacytomas from uracil N -glycosylase and activation-induced cytidine deaminase-deficient mice. Mapping of translocation breakpoints using an acetylated histone H3 lysine 9 chromatin immunoprecipitation sequencing approach reveals Igh fusions up to ∼350 kb upstream of Myc or the related oncogene Mycn . A comprehensive analysis of epigenetic marks, PolII recruitment, and transcription in tumor cells demonstrates that the 3′ Igh enhancer (Eα) vastly remodels ∼450 kb of chromatin into translocated sequences, leading to significant polymerase occupancy and constitutive oncogene expression. We show that this long-range epigenetic reprogramming is directly proportional to the physical interaction of Eα with translocated sites. Our studies thus uncover the extent of epigenetic remodeling by Ig 3′ enhancers and provide a rationale for the long-range deregulation of translocated oncogenes in endemic Burkitt lymphomas. The data also shed light on the origin of endemic-like chromosomal rearrangements.