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. 2009 Feb 17;106(7):2265-70.
doi: 10.1073/pnas.0812763106. Epub 2009 Jan 27.

Chromosomal location targets different MYC family gene members for oncogenic translocations

Monica Gostissa  1 , Sheila Ranganath, Julia M Bianco, Frederick W Alt
Affiliations

Chromosomal location targets different MYC family gene members for oncogenic translocations

Monica Gostissa et al. Proc Natl Acad Sci U S A. .

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
LPMycN/+ and LPMycN/N mice develop pro-B cell lymphomas. (A) Kaplan–Meier curves of the LPMycN/+ (n = 21) and LPMycN/N (n = 9) cohorts are shown. The curves represent tumor-free survival. (B) Surface marker expression in LPMycN/+ and LPMycN/N tumors was analyzed by cytofluorimetry with B220/IgM (Top) or CD4/CD8 (Bottom) antibodies. C, control; spl, spleen; pLN, peripheral lymph nodes; thy, thymus. Representative cases are shown.
Fig. 2.
Fig. 2.
The NCR locus is amplified in LPMycN/+ and LPMycN/N tumors. (A) Schematic representation of the endogenous c-Myc and targeted NCR loci. Positions of relevant restriction sites and probes used are shown. (B) Southern blot analysis of LPMycN/+ tumor DNA digested by EcoRI (ERI) restriction enzyme. Probes used are indicated at the bottom of each panel. Positions of the WT c-Myc (Top) and germ-line IgH (Middle) bands are indicated. Loading of an equal amount of DNA in each lane was confirmed by using a control probe (Bottom) hybridizing to the MDC1 gene. (C) Southern blot analysis of LPMycN/+ tumor DNA digested by BamHI (BHI) restriction enzyme and analyzed with Myc 3′ probe. Positions of the WT c-Myc and NCR bands are indicated. (D) Southern blot analysis of LPMycN/N tumor DNA. Restriction enzymes and probes used are indicated at the bottom of each panel. Positions of the WT c-Myc and NCR bands (Top) and germ-line IgH band (Bottom) are indicated.
Fig. 3.
Fig. 3.
LPMycN/+ and LPMycN/N tumors harbor characteristic c12;15 and t12;15 translocations. (A) FISH and chromosome paint analysis of metaphases from selected LPMycN/+ and LPMycN/N tumors. The same metaphase was sequentially analyzed with a different set of probes as indicated at the top of each panel. Note that the red signal from the second hybridization was not efficiently stripped and still shows in the third set of images. Results from chromosome paint hybridization were confirmed on an independent set of metaphases for all tumors analyzed (not shown). A schematic of the different chromosomal species detected is shown at the Top. (B) Summary of FISH and chromosome paint analyses on additional LPMycN/+ tumors. Only chromosomes involved in translocations are shown. Sequential hybridization with the set of probes indicated at the top was performed. A graphic representation of the translocations observed in each case is shown.
Fig. 4.
Fig. 4.
Characterization of LPMycN/+ and LPMycN/N tumors lacking Myc amplification. (A) Southern blot analysis of DNA from tumors 617, 619 (LPMycN/+) and 871, 215 (LPMycN/N) with probes specific for the 5′ region of the c-Myc locus (MycA, Left panel) and for the N-myc locus (Right panel). Positions of the WT c-Myc, WT N-myc, and NCR bands are indicated. Loading of an equal amount of DNA in each lane was confirmed by using a control probe (Right Bottom panel) hybridizing to the MDC1 gene. (B) SKY analysis on tumor 617. One representative metaphase is shown. The arrows indicate chromosomes involved in clonal translocations. A detailed view of these chromosomes is presented in the panels on the Right, showing DAPI, spectral, and computer-classified staining for each chromosome. (C) SKY analysis on tumor 619. One representative metaphase is shown. The arrow indicates the chromosome involved in clonal translocation. The complete karyotype (computer-classified staining) and details of the 16;4 translocations are shown.
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