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The 3' IgH Locus Control Region Is Sufficient to Deregulate a c-myc Transgene and Promote Mature B Cell Malignancies with a Predominant Burkitt-Like Phenotype¹

Véronique Truffinet^*, Eric Pinaud^*, Nadine Cogné^*, Barbara Petit^*,, Laurence Guglielmi^2,*, Michel Cogné^* and Yves Denizot^3,*

^* Unité Mixte de Recherche, Centre National de la Recherche Scientifique 6101, Université de Limoges, Limoges, France; and Service d’Anatomie Pathologique, University Hospital, Limoges, France

Burkitt lymphoma (BL) features translocations linking c-myc to an Ig locus. Breakpoints in the H chain locus (IgH) stand either close to J_H or within switch regions and always link c-myc to the 3' IgH locus control region (3' LCR). To test the hypothesis that the 3' LCR alone was sufficient to deregulate c-myc, we generated mice carrying a 3' LCR-driven c-myc transgene and specifically up-regulating c-myc in B cells. Splenic B cells from mice proliferated exaggeratedly in response to various signals had an elevated apoptosis rate but normal B220/IgM/IgD expression. Although all Ig levels were lowered in vivo, class switching and Ig secretion proved normal in vitro. Beginning at the age of 12 wk, transgenic mice developed clonal lymphoblastic lymphomas or diffuse anaplastic plasmacytomas with an overall incidence of 80% by 40 wk. Lymphoblastic lymphomas were B220⁺IgM⁺IgD⁺ with the BL "starry sky" appearance. Gene expression profiles revealed broad alterations in the proliferation program and the Ras-p21 pathway. Our study demonstrates that 3' IgH enhancers alone can deregulate c-myc and initiate the development of BL-like lymphomas. The rapid and constant occurrence of lymphoma in this model makes it valuable for the understanding and the potential therapeutic manipulation of c-myc oncogenicity in vivo.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Ligue Nationale contre le Cancer, Conseil Régional du Limousin, and "Lions Club de la Corrèze, Zone 33 district 103 Sud."

² Current address: Institut National de la Santé et de la Recherche Médicale Unité 454, Centre Hospitalier de l’Université Arnaud de Villeneuve, Montpellier, France.

³ Address correspondence and reprint requests to Dr. Yves Denizot, Faculté Médecine, Laboratoire d’Immunologie, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 6101, 2 rue Dr. Marcland, 87025, Limoges, France. E-mail address: yves.denizot{at}unilim.fr

⁴ Abbreviations used in this paper: BL, Burkitt lymphoma; LCR, locus control region; CSR, class switch recombination; ES, embryonic stem; wt, wild type; WBC, white blood cell.

⁵ The online version of this article contains supplemental material.

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The JI 2007 179: 5615-5616. [Full Text]