Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells - PubMed (original) (raw)
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. 2004.
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.
Figures
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.
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.
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.
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.
_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.
Similar articles
- Evidence for replicative repair of DNA double-strand breaks leading to oncogenic translocation and gene amplification.
Difilippantonio MJ, Petersen S, Chen HT, Johnson R, Jasin M, Kanaar R, Ried T, Nussenzweig A. Difilippantonio MJ, et al. J Exp Med. 2002 Aug 19;196(4):469-80. doi: 10.1084/jem.20020851. J Exp Med. 2002. PMID: 12186839 Free PMC article. - Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching.
Wang JH, Alt FW, Gostissa M, Datta A, Murphy M, Alimzhanov MB, Coakley KM, Rajewsky K, Manis JP, Yan CT. Wang JH, et al. J Exp Med. 2008 Dec 22;205(13):3079-90. doi: 10.1084/jem.20082271. Epub 2008 Dec 8. J Exp Med. 2008. PMID: 19064702 Free PMC article. - Amplification of IGH/MYC fusion in clinically aggressive IGH/BCL2-positive germinal center B-cell lymphomas.
Martín-Subero JI, Odero MD, Hernandez R, Cigudosa JC, Agirre X, Saez B, Sanz-García E, Ardanaz MT, Novo FJ, Gascoyne RD, Calasanz MJ, Siebert R. Martín-Subero JI, et al. Genes Chromosomes Cancer. 2005 Aug;43(4):414-23. doi: 10.1002/gcc.20187. Genes Chromosomes Cancer. 2005. PMID: 15852472 - Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations.
Zhu C, Mills KD, Ferguson DO, Lee C, Manis J, Fleming J, Gao Y, Morton CC, Alt FW. Zhu C, et al. Cell. 2002 Jun 28;109(7):811-21. doi: 10.1016/s0092-8674(02)00770-5. Cell. 2002. PMID: 12110179 - Myc translocations in B cell and plasma cell neoplasms.
Janz S. Janz S. DNA Repair (Amst). 2006 Sep 8;5(9-10):1213-24. doi: 10.1016/j.dnarep.2006.05.017. Epub 2006 Jul 11. DNA Repair (Amst). 2006. PMID: 16815105 Review.
Cited by
- Exonucleases: Degrading DNA to Deal with Genome Damage, Cell Death, Inflammation and Cancer.
Manils J, Marruecos L, Soler C. Manils J, et al. Cells. 2022 Jul 9;11(14):2157. doi: 10.3390/cells11142157. Cells. 2022. PMID: 35883600 Free PMC article. Review. - DNA damage-induced phosphorylation of CtIP at a conserved ATM/ATR site T855 promotes lymphomagenesis in mice.
Wang XS, Menolfi D, Wu-Baer F, Fangazio M, Meyer SN, Shao Z, Wang Y, Zhu Y, Lee BJ, Estes VM, Cupo OM, Gautier J, Pasqualucci L, Dalla-Favera R, Baer R, Zha S. Wang XS, et al. Proc Natl Acad Sci U S A. 2021 Sep 21;118(38):e2105440118. doi: 10.1073/pnas.2105440118. Proc Natl Acad Sci U S A. 2021. PMID: 34521752 Free PMC article. - Cell circuits and niches controlling B cell development.
Zehentmeier S, Pereira JP. Zehentmeier S, et al. Immunol Rev. 2019 May;289(1):142-157. doi: 10.1111/imr.12749. Immunol Rev. 2019. PMID: 30977190 Free PMC article. Review. - MRE11 Promotes Tumorigenesis by Facilitating Resistance to Oncogene-Induced Replication Stress.
Spehalski E, Capper KM, Smith CJ, Morgan MJ, Dinkelmann M, Buis J, Sekiguchi JM, Ferguson DO. Spehalski E, et al. Cancer Res. 2017 Oct 1;77(19):5327-5338. doi: 10.1158/0008-5472.CAN-17-1355. Epub 2017 Aug 17. Cancer Res. 2017. PMID: 28819025 Free PMC article. - p53 in the DNA-Damage-Repair Process.
Williams AB, Schumacher B. Williams AB, et al. Cold Spring Harb Perspect Med. 2016 May 2;6(5):a026070. doi: 10.1101/cshperspect.a026070. Cold Spring Harb Perspect Med. 2016. PMID: 27048304 Free PMC article. Review.
References
- Bassing, C. H., Swat, W. & Alt, F. W. (2002) Cell 109, S45–S55. - PubMed
- Ma, Y., Pannicke, U., Schwarz, K. & Lieber, M. R. (2002) Cell 108, 781–794. - PubMed
- Rooney, S., Sekiguchi, J., Zhu, C., Cheng, H. L., Manis, J., Whitlow, S., DeVido, J., Foy, D., Chaudhuri, J., Lombard, D. & Alt, F. W. (2002) Mol. Cell 10, 1379–1390. - PubMed
- Zhu, C. & Roth, D. B. (1995) Immunity 2, 101–112. - PubMed
- Frank, K. M., Sharpless, N. E., Gao, Y., Sekiguchi, J. M., Ferguson, D. O., Zhu, C., Manis, J. P., Horner, J., DePinho, R. A. & Alt, F. W. (2000) Mol. Cell 5, 993–1002. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- K08 HL067580/HL/NHLBI NIH HHS/United States
- P01 AI035714/AI/NIAID NIH HHS/United States
- P01 CA092625/CA/NCI NIH HHS/United States
- AI35714/AI/NIAID NIH HHS/United States
- CA92625/CA/NCI NIH HHS/United States
- K08 HL67580-02/HL/NHLBI NIH HHS/United States
LinkOut - more resources
Full Text Sources
Molecular Biology Databases
Research Materials
Miscellaneous