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. 2004 Feb 24;101(8):2410-5.
doi: 10.1073/pnas.0308757101.

Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells

Sean Rooney  1 , JoAnn Sekiguchi, Scott Whitlow, Mark Eckersdorff, John P Manis, Charles Lee, David O Ferguson, Frederick W Alt
Affiliations

Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells

Sean Rooney et al. Proc Natl Acad Sci U S A. .

Abstract

The nonhomologous DNA end-joining (NHEJ) pathway contains six known components, including Artemis, a nuclease mutated in a subset of human severe combined immunodeficient patients. Mice doubly deficient for the five previously analyzed NHEJ factors and p53 inevitably develop progenitor B lymphomas harboring der(12)t(12;15) translocations and immunoglobin heavy chain (IgH)/c-myc coamplification mediated by a breakage-fusion-bridge mechanism. In this report, we show that Artemis/p53-deficient mice also succumb reproducibly to progenitor B cell tumors, demonstrating that Artemis is a tumor suppressor in mice. However, the majority of Artemis/p53-deficient tumors lacked der(12)t(12;15) translocations and c-myc amplification and instead coamplified IgH and N-myc through an intra- or interchromosome 12 breakage-fusion-bridge mechanism. We discuss this finding in the context of potential implications for mechanisms that may target IgH locus translocations to particular oncogenes.

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Figures

Fig. 1.
Fig. 1.
Increased mortality in AN/NpN/N double-deficient mice. Shown is a Kapplan–Meier curve representing the percent survival of AN/+pN/+ (n = 12), AN/NpN/+ (n = 17), AN/+pN//N(n = 19), and AN/NpN/N(n = 19) cohort mice versus age in days.
Fig. 2.
Fig. 2.
A majority of AN/NpN/N pro-B cell tumors are cytogenetically distinct from other NHEJ/p53 tumors. Shown are SKY images of metaphase spreads from AP87, representative of the majority of AN/NpN/N pro-B cell tumors harboring a novel aberration, presenting as an enlarged copy of chromosome 12. SKY images are on the left, 4′,6-diamidino-2-phenylindole-stained images are in the middle, and computer-classified colors are on the right.
Fig. 3.
Fig. 3.
IgH and N-myc are coamplified on chromosome 12. (A) Representative FISH (Left) and SKY (Right) analyses of three tumors (AP 145, AP269, and AP270) exhibiting N-myc amplification by Southern blotting. The IgH FISH probe is red, the N-myc probe is green, and regions of coamplification are highlighted by yellow arrows. (B) Representative FISH (Upper, Lower Left) and SKY (Lower Right) analyses of tumor AP138 that exhibits c-myc amplification by Southern blotting. The IgH FISH probe is red, and the c-myc (Upper) or N-myc (Lower Left) is green. (C) Representative metaphase from AP270 analysis with a chromosome 12 paint (red) and the N-myc FISH probe (green).
Fig. 4.
Fig. 4.
N-myc is amplified in a majority of AN/NpN/N pro-B cell tumors. (A and B) Southern blot analyses of tumor samples and kidney sample from a control mouse with a JH1.1 probe (A) or a N-myc probe and a c-myc probe (B). The LR8 control probe was used as a loading control to measure the amplification of relevant sequences. (C) Northern blot analysis of RNA isolated from tumors along with wild-type thymus probed with a c-myc or N-myc probe.
Fig. 5.
Fig. 5.
N-myc amplification is initiated by the translocation of IgH sequence around N-myc. (A) Schematic representation of chromosome 12 and 15 showing breakpoints of indicated tumors within the JH locus and N-myc (chr 12) or c-myc (chr 15). Breakpoint no. 4 (AP270) represents a DHJH rearrangement translocated telomeric to N-myc. (B) Sequences of the cloned translocation breakpoints from AN/NpN/N pro-B cell tumors. AP87, AP269, AP145, and AP270 have N-myc amplification, and AP138 is amplified for c-myc. JH sequences are in red, N-myc sequences are in green, and c-myc sequences are in black. Regions of homology are in blue, and nontemplated nucleotides are in purple. The locations and orientation of the translocation breakpoints are indicated to the right. TEL, telomeric; CEN, centromeric.
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