Uncoupling between Ig somatic hypermutation and oncogene mutation in mouse lymphoma.
Burkitt lymphoma (BL) features translocations linking c-myc to the immunoglobulin heavy chain (IgH) locus. By inserting a c-myc gene under the control of the 3'IgH locus control region (LCR) into the mouse genome, we generated c-myc-3'LCR mice that develop clonal BL or diffuse anaplastic lymphoma. We show in the present study that while BL from c-myc-3'LCR mice would be classified as pre-germinal center (GC) cells due to the absence of both BCL-6 expression and somatic hypermutation (SHM) in V(H) sequences, they show a high level of SHM focused on the c-myc oncogene itself. This observation suggests that the c-myc-3'IgH LCR tandem association drives development of lymphoma from naïve B cells by specifically recruiting AID activity on c-myc in a process that early becomes independent from antigen selection and where the successive rounds of SHM rather rely on the selection of the most efficient mutations for oncogene deregulation. Similar to the translocated c-myc gene in human BL, mutations were found in first exon and 5' flanking sequences of transgenic c-myc and specially focused on negative regulatory elements, thus leading to high and constitutive oncogene expression. In conclusion while 3'IgH transcriptional enhancers in c-myc-3'LCR mice first simply act in cis to slightly stimulate c-myc transcription in untransformed B cells, the occurrence of lymphoma appears to result from an additional mechanism necessitating AID-driven mutations within the first exon and 5' flanking sequences which does not occur in parallel but rather circumvents antigen-driven selection.
Vincent
Christelle
C
UMR CNRS 6101, Centre National de la Recherche Scientifique, Université de Limoges, France.
Truffinet
Véronique
V
Fiancette
Remi
R
Petit
Barbara
B
Cogné
Nadine
N
Cogné
Michel
M
Denizot
Yves
Y
D024506:5' Flanking Region / Q000235:genetics; D000818:Animals; D002051:Burkitt Lymphoma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005091:Exons / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc / Q000235:genetics*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D019901:Locus Control Region / Q000235:genetics; D008223:Lymphoma / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics*
C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger