Chromosomal location targets different MYC family gene members for oncogenic translocations

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 7; pp. 2265 - 2270
• Main Authors: Gostissa, Monica, Ranganath, Sheila, Bianco, Julia M, Alt, Frederick W
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 17.02.2009; National Acad Sciences
• Subjects: Alleles; Animal models; Animals; Apoptosis; Biological Sciences; c-Myc protein; Cancer; Cell culture; Cell growth; Cell proliferation; Cells; Chromosome Aberrations; Chromosome translocation; Chromosome translocations; Chromosomes; Chromosomes - ultrastructure; Coding; Deoxyribonucleic acid; DNA; DNA - metabolism; DNA Ligase ATP; DNA Ligases - genetics; DNA Ligases - metabolism; DNA probes; Enzymes; Flow Cytometry; Gene Expression Regulation, Neoplastic; Genes; Genetic loci; Heterozygote; Homozygote; Humans; LIG4 protein; Lymphoma; Malignancy; Mice; myc genes; Myc protein; N-Myc protein; Neuroblastoma; Oncogenes; p53 protein; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Stem cells; Transcription; Transcription activation; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0812763106

The MYC family of cellular oncogenes includes c-Myc, N-myc, and L-myc, which encode transcriptional regulators involved in the control of cell proliferation and death. Accordingly, these genes become aberrantly activated and expressed in specific types of cancers. For example, c-Myc translocations occur frequently in human B lymphoid tumors, while N-myc gene amplification is frequent in human neuroblastomas. The observed association between aberrations in particular MYC family genes and specific subsets of malignancies might reflect, at least in part, tissue-specific differences in expression or function of a given MYC gene. Since c-Myc and N-myc share substantial functional redundancy, another factor that could influence tumor-specific gene activation would be mechanisms that target aberrations (e.g., translocations) in a given MYC gene in a particular tumor progenitor cell type. We have previously shown that mice deficient for the DNA Ligase4 (Lig4) nonhomologous DNA end-joining factor and the p53 tumor suppressor routinely develop progenitor (pro)-B cell lymphomas that harbor translocations leading to c-Myc amplification. Here, we report that a modified allele in which the c-Myc coding sequence is replaced by N-myc coding sequence (NCR allele) competes well with the wild-type c-Myc allele as a target for oncogenic translocations and amplifications in the Lig4/p53-deficient pro-B cell lymphoma model. Tumor onset, type, and cytological aberrations are similar in tumors harboring either the wild-type c-Myc gene or the NCR allele. Our results support the notion that particular features of the c-Myc locus select it as a preferential translocation/amplification target, compared to the endogenous N-myc locus, in Lig4/p53-deficient pro-B cell lymphomas.