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PMID: 17998390 Published · ppublish English Journal Article Research Support, N.I.H., Intramural

AID-deficient Bcl-xL transgenic mice develop delayed atypical plasma cell tumors with unusual Ig/Myc chromosomal rearrangements.

The Journal of experimental medicine ·Vol. 204 ·No. 12 ·2007-11-26 ·Pages 2989-3001

Kovalchuk AL, duBois W, Mushinski E, McNeil NE, Hirt C, Qi CF, Li Z, Janz S, Honjo T, Muramatsu M, Ried T, Behrens T, Potter M

Abstract

Activation-induced cytidine deaminase (AID) is required for immunoglobulin (Ig) class switch recombination and somatic hypermutation, and has also been implicated in translocations between Ig switch regions and c-Myc in plasma cell tumors in mice. We asked if AID is required for accelerated tumor development in pristane-treated Bcl-xL transgenic BALB/c mice deficient in AID (pBxAicda-/-). pBxAicda-/- mice developed tumors with a lower frequency (24 vs. 62%) and a longer mean latency (108 vs. 36 d) than AID-sufficient mice. The tumors appeared in oil granuloma tissue and did not form ascites. By interphase fluorescence in situ hybridization, six out of nine pBxAicda-/- primary tumors had T(12;15) and one had T(6;15) chromosomal translocations. Two tumors were transplantable and established as stable cell lines. Molecular and cytogenetic analyses showed that one had an unusual unbalanced T(12;15) translocation, with IgH Cmu and Pvt-1 oriented head to tail at the breakpoint, resulting in an elevated expression of c-Myc. In contrast, the second was T(12;15) negative, but had an elevated N-Myc expression caused by a paracentric inversion of chromosome 12. Thus, novel mechanisms juxtapose Ig and Myc-family genes in AID-deficient plasma cell tumors.

MeSH Terms
Animals Cytidine Deaminase/deficiency,genetics Gene Rearrangement Genes, Immunoglobulin Genes, myc Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Inbred DBA Mice, Knockout Mice, Transgenic Neoplasms, Plasma Cell/genetics,prevention & control bcl-X Protein/deficiency,genetics
Chemicals
Bcl2l1 protein, mouse bcl-X Protein AICDA (activation-induced cytidine deaminase) Cytidine Deaminase
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Kovalchuk Alexander L
Laboratory of Cancer Biology and Genetics, Cancer Genomics Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
duBois Wendy
Mushinski Elizabeth
McNeil Nicole E
Hirt Carsten
Qi Chen-Feng
Li Zhaoyang
Janz Siegfried
Honjo Tasuku
Muramatsu Masamichi
Ried Thomas
Behrens Timothy
Potter Michael
References (68)
68 references, click to expand
  1. Mechanisms of nonhomologous recombination in mammalian cells.
    Mol Cell Biol. 1985 Oct;5(10):2599-607 PMID: 3016509
  2. H2AX haploinsufficiency modifies genomic stability and tumor susceptibility.
    Cell. 2003 Aug 8;114(3):371-383 PMID: 12914701
  3. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death.
    Cell. 1993 Aug 27;74(4):597-608 PMID: 8358789
  4. Differences in the peritoneal response to pristane in BALB/cAnPt and BALB/cJ mice.
    Curr Top Microbiol Immunol. 1985;122:242-53 PMID: 2412763
  5. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2).
    Cell. 2000 Sep 1;102(5):565-75 PMID: 11007475
  6. Induction of apoptosis in fibroblasts by c-myc protein.
    Cell. 1992 Apr 3;69(1):119-28 PMID: 1555236
  7. Self-reactive B lymphocytes overexpressing Bcl-xL escape negative selection and are tolerized by clonal anergy and receptor editing.
    Immunity. 1998 Jul;9(1):35-45 PMID: 9697834
  8. Requirement of non-canonical activity of uracil DNA glycosylase for class switch recombination.
    J Biol Chem. 2007 Jan 5;282(1):731-42 PMID: 17090531
  9. Plasmacytomagenesis in mice: model of neoplastic development dependent upon chromosomal translocations.
    Carcinogenesis. 1992 Oct;13(10):1681-97 PMID: 1423827
  10. AID is required for c-myc/IgH chromosome translocations in vivo.
    Cell. 2004 Aug 20;118(4):431-8 PMID: 15315756
  11. Pathways that suppress programmed DNA breaks from progressing to chromosomal breaks and translocations.
    DNA Repair (Amst). 2006 Sep 8;5(9-10):1030-41 PMID: 16934538
  12. Constitutive histone H2AX phosphorylation and ATM activation, the reporters of DNA damage by endogenous oxidants.
    Cell Cycle. 2006 Sep;5(17):1940-5 PMID: 16940754
  13. Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells.
    J Biol Chem. 1999 Jun 25;274(26):18470-6 PMID: 10373455
  14. bcl-x exhibits regulated expression during B cell development and activation and modulates lymphocyte survival in transgenic mice.
    J Exp Med. 1996 Feb 1;183(2):381-91 PMID: 8627151
  15. Mutations in the p53 and SCID genes cooperate in tumorigenesis.
    Genes Dev. 1996 Aug 15;10(16):2055-66 PMID: 8769648
  16. AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification.
    Nature. 2002 Jul 4;418(6893):99-103 PMID: 12097915
  17. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53.
    Cell. 1992 Sep 18;70(6):923-35 PMID: 1356076
  18. Generation of plasmacytomas with the chromosomal translocation t(12;15) in interleukin 6 transgenic mice.
    Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):232-5 PMID: 1729694
  19. DNA damage induced by phorbol ester-stimulated neutrophils is augmented by extracellular cofactors. Role of histidine and metals.
    J Biol Chem. 1990 Apr 25;265(12):6693-9 PMID: 2157707
  20. Roles of nonhomologous DNA end joining, V(D)J recombination, and class switch recombination in chromosomal translocations.
    DNA Repair (Amst). 2006 Sep 8;5(9-10):1234-45 PMID: 16793349
  21. Phagocytes as carcinogens: malignant transformation produced by human neutrophils.
    Science. 1985 Mar 8;227(4691):1231-3 PMID: 3975611
  22. BCL2 accelerates inflammation-induced BALB/c plasmacytomas and promotes novel tumors with coexisting T(12;15) and T(6;15) translocations.
    Cancer Res. 2003 Dec 15;63(24):8656-63 PMID: 14695177
  23. Genetic pathway to recurrent chromosome translocations in murine lymphoma involves V(D)J recombinase.
    J Clin Invest. 1999 Jun;103(12):1669-75 PMID: 10377173
  24. De novo protein synthesis is required for the activation-induced cytidine deaminase function in class-switch recombination.
    Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2634-8 PMID: 12591955
  25. Multicolour spectral karyotyping of mouse chromosomes.
    Nat Genet. 1996 Nov;14(3):312-5 PMID: 8896561
  26. Novel targeted deregulation of c-Myc cooperates with Bcl-X(L) to cause plasma cell neoplasms in mice.
    J Clin Invest. 2004 Jun;113(12):1763-73 PMID: 15199411
  27. Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors.
    Cell. 2003 Aug 8;114(3):359-70 PMID: 12914700
  28. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme.
    Cell. 2000 Sep 1;102(5):553-63 PMID: 11007474
  29. Juxtaposition of N-myc and Ig kappa through a reciprocal t(6;12) translocation in a mouse plasmacytoma.
    Genes Chromosomes Cancer. 1994 Oct;11(2):85-90 PMID: 7529553
  30. A novel c-myc-activating reciprocal T(12;15) chromosomal translocation juxtaposes S alpha to Pvt-1 in a mouse plasmacytoma.
    Oncogene. 1994 Jan;9(1):247-53 PMID: 8302586
  31. Differences between Burkitt's lymphomas and mouse plasmacytomas in the immunoglobulin heavy chain/c-myc recombinations that occur in their chromosomal translocations.
    Cancer Res. 1995 Nov 1;55(21):5012-8 PMID: 7585544
  32. Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer.
    Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12871-6 PMID: 14566050
  33. Amplifying mechanisms of lymphomagenesis.
    Mol Cell. 2002 Jul;10(1):1-2 PMID: 12150897
  34. Role of oxygen radicals in DNA damage and cancer incidence.
    Mol Cell Biochem. 2004 Nov;266(1-2):37-56 PMID: 15646026
  35. Activation of the c-myc oncogene by the immunoglobulin heavy-chain gene enhancer after multiple switch region-mediated chromosome rearrangements in a murine plasmacytoma.
    Proc Natl Acad Sci U S A. 1985 Jun;82(11):3746-50 PMID: 2987943
  36. DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation.
    Nature. 2000 Mar 30;404(6777):510-4 PMID: 10761921
  37. Frequent aberrant immunoglobulin gene rearrangements in pro-B cells revealed by a bcl-xL transgene.
    Immunity. 1996 Mar;4(3):291-9 PMID: 8624819
  38. DNA damage responses to oxidative stress.
    DNA Repair (Amst). 2004 Aug-Sep;3(8-9):1109-15 PMID: 15279799
  39. Lymph nodes and Peyer's patches of IL-6 transgenic BALB/c mice harbor T(12;15) translocated plasma cells that contain illegitimate exchanges between the immunoglobulin heavy-chain mu locus and c-myc.
    Leukemia. 2000 Jun;14(6):1127-35 PMID: 10865979
  40. Lymphoid neogenesis in chronic inflammatory diseases.
    Nat Rev Immunol. 2006 Mar;6(3):205-17 PMID: 16498451
  41. Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles.
    Cell. 1992 Sep 18;70(6):937-48 PMID: 1525830
  42. Identification of an AID-independent pathway for chromosomal translocations between the Igh switch region and Myc.
    Nat Immunol. 2004 Nov;5(11):1117-23 PMID: 15489857
  43. 53BP1 cooperates with p53 and functions as a haploinsufficient tumor suppressor in mice.
    Mol Cell Biol. 2005 Nov;25(22):10079-86 PMID: 16260621
  44. Quantitation of immunoglobulin mu-gamma 1 heavy chain switch region recombination by a digestion-circularization polymerase chain reaction method.
    Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6978-82 PMID: 1495989
  45. E mu-bcl-2 transgene facilitates spontaneous transformation of early pre-B and immunoglobulin-secreting cells but not T cells.
    Oncogene. 1993 Jan;8(1):1-9 PMID: 8423986
  46. Transposition of the immunoglobulin heavy chain enhancer to the myc oncogene in a murine plasmacytoma.
    Cell. 1985 Jan;40(1):71-9 PMID: 2981633
  47. Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells.
    Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2410-5 PMID: 14983023
  48. Activation of cellular oncogenes in hemopoietic cells by chromosome translocation.
    Adv Cancer Res. 1986;47:189-234 PMID: 3096089
  49. Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations.
    Cell. 2002 Jun 28;109(7):811-21 PMID: 12110179
  50. Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine.
    J Immunol. 2002 Jan 1;168(1):57-64 PMID: 11751946
  51. Mouse plasmacytoma associated (MPC) T(15;16) translocation occurs repeatedly in new MPC induction system.
    Curr Top Microbiol Immunol. 1990;166:107-19 PMID: 2073788
  52. Withdrawal symptoms on display: Bcl-2 members under investigation.
    Trends Immunol. 2007 Jan;28(1):26-32 PMID: 17129763
  53. Clonal diversification of primary BALB/c plasmacytomas harboring T(12;15) chromosomal translocations.
    Leukemia. 2000 May;14(5):909-21 PMID: 10803525
  54. Lymphoid organ development: from ontogeny to neogenesis.
    Nat Immunol. 2006 Apr;7(4):344-53 PMID: 16550197
  55. Role of genomic instability and p53 in AID-induced c-myc-Igh translocations.
    Nature. 2006 Mar 2;440(7080):105-9 PMID: 16400328
  56. H2AX: the histone guardian of the genome.
    DNA Repair (Amst). 2004 Aug-Sep;3(8-9):959-67 PMID: 15279782
  57. Switching on chromosomal translocations.
    Cancer Res. 2006 Aug 15;66(16):7837-9 PMID: 16912154
  58. c-myc gene in a murine plasmocytoma without visible chromosomal translocations moves to chromosome 12F1 with Pvt-1 and rearranges with IgH enhancer-S mu sequences.
    Int J Cancer. 1991 Aug 19;49(1):102-8 PMID: 1874562
  59. Constitutive c-myc expression in an IL-3-dependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis.
    Oncogene. 1991 Oct;6(10):1915-22 PMID: 1923514
  60. Nonrandom chromosome changes involving the Ig gene-carrying chromosomes 12 and 6 in pristane-induced mouse plasmacytomas.
    Cell. 1979 Dec;18(4):1001-7 PMID: 519762
  61. Evidence for replicative repair of DNA double-strand breaks leading to oncogenic translocation and gene amplification.
    J Exp Med. 2002 Aug 19;196(4):469-80 PMID: 12186839
  62. Specific pathogen-free BALB/cAn mice are refractory to plasmacytoma induction by pristane.
    J Immunol. 1991 Nov 15;147(10):3632-7 PMID: 1682379
  63. Critical roles of activation-induced cytidine deaminase in the homeostasis of gut flora.
    Science. 2002 Nov 15;298(5597):1424-7 PMID: 12434060
  64. The nonhomologous end joining factor Artemis suppresses multi-tissue tumor formation and prevents loss of heterozygosity.
    Oncogene. 2007 Sep 6;26(41):6010-20 PMID: 17384673
  65. A complex translocation at the murine kappa light-chain locus.
    Mol Cell Biol. 1987 Nov;7(11):4130-3 PMID: 3123918
  66. Functional homology between N-myc and c-myc in murine plasmacytomagenesis: plasmacytoma development in N-myc transgenic mice.
    Oncogene. 1992 Jun;7(6):1241-7 PMID: 1375720
  67. The p53 tumor suppressor participates in multiple cell cycle checkpoints.
    J Cell Physiol. 2006 Oct;209(1):13-20 PMID: 16741928
  68. Activated neutrophils induce prolonged DNA damage in neighboring cells.
    Carcinogenesis. 1988 Dec;9(12):2297-304 PMID: 2847879
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
1540-9538
DOI
10.1084/jem.20070882
Published
2007-11-26
Epub
2007-00-06
Pages
2989-3001
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2118515
Subset
IM
Grants
Intramural NIH HHS · United States
External Links
PubMed source DOI: 10.1084/jem.20070882 PMC Full Text View journal details
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