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 phenotype.
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.
Truffinet
Véronique
V
Unité Mixte de Recherche, Centre National de la Recherche Scientifique 6101, Université de Limoges, Limoges, France.
Pinaud
Eric
E
Cogné
Nadine
N
Petit
Barbara
B
Guglielmi
Laurence
L
Cogné
Michel
M
Denizot
Yves
Y
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000473:pathology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D015996:Survival Rate; D014158:Transcription, Genetic / Q000235:genetics; D019076:Transgenes / Q000235:genetics*
D007143:Immunoglobulin Heavy Chains; D016271:Proto-Oncogene Proteins c-myc