title: Chromosomal location targets different MYC family gene members for oncogenic translocations.
abstract: 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.
authors.affiliation: The Howard Hughes Medical Institute, Children's Hospital Boston, and Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Gostissa
authors.forename: Sheila
authors.initials: S
authors.lastname: Ranganath
authors.forename: Julia M
authors.initials: JM
authors.lastname: Bianco
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
mesh_terms: D000483:Alleles; D000818:Animals; D002869:Chromosome Aberrations; D002875:Chromosomes / Q000648:ultrastructure*; D004247:DNA / Q000378:metabolism; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D051379:Mice; D009857:Oncogenes; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: C000607893:LIG4 protein, human; D016271:Proto-Oncogene Proteins c-myc; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004247:DNA; D011088:DNA Ligases; D000072481:DNA Ligase ATP