Genomic instability in mouse Burkitt lymphoma is dominated by illegitimate genetic recombinations, not point mutations

• Published in: Oncogene Vol. 21; no. 47; pp. 7235 - 7240
• Main Authors: Rockwood, Lynne D, Torrey, Ted A, Kim, Joong Su, Coleman, Allen E, Kovalchuk, Alexander L, Xiang, Shao, Ried, Thomas, Morse, 3rd, Herbert C, Janz, Siegfried
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 17.10.2002
• Subjects: Animals; Burkitt Lymphoma - genetics; Burkitt's lymphoma; Cancer; Cell Line; Chromosome translocations; Gene mutations; Genes, Immunoglobulin; Genes, myc - physiology; Genes, p16; Genes, Reporter; Genetic aspects; Genomic instability; Genotype & phenotype; Health aspects; INK4a protein; Lac Operon; Liver; Lymphatic system; Lymphoma; Mice; Mice, Transgenic; Mutagenesis; Mutant frequency; Mutation; Myc protein; p16 Protein; Phenotypes; Point Mutation; Proto-oncogenes; Recombination, Genetic; Reporter gene; Risk factors; Spleen; Tumor suppressor genes; Tumorigenesis; Tumors; United States; United States > US; Maryland
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1205697

lambda-MYC-induced mouse Burkitt lymphoma (BL) harboring the shuttle vector pUR288, which includes a lacZ reporter gene to study mutagenesis, was employed to assess genomic instability associated with MYC deregulation. The frequency of lacZ mutations in lymphomas was elevated only 1.75-fold above that in normal tissue, indicating that mouse BL does not exhibit a phenotype of hypermutability. However, the nature of lacZ mutations was strikingly different in normal tissues and lymphomas. While point mutations comprised approximately 75% of the mutations found in normal tissues, apparent translocations, deletions and inversions constituted the majority of mutations ( approximately 65%) in lymphomas. Genomic instability in mouse BL thus seems characterized by a preponderance of illegitimate genetic rearrangements in the context of near-background mutant frequencies. SKY analyses of cell lines from primary BL tumors revealed substantial changes in chromosomal structure, confirming the lacZ studies. Bi-allelic deletions of the tumor suppressor p16(Ink4a) were detected in six out of 16 cell lines, illustrating cellular selection of advantageous mutations. Together, these approaches indicate that MYC may contribute to lymphomagenesis through the dominant mutator effect of inducing chromosomal instability. The results further suggest that a phenotype of hypermutability (elevated mutant frequency) may not always be required for oncogenesis to occur.