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AID Biology: A pathological and clinical perspective

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Pages 37-56 | Received 06 Jul 2017, Accepted 17 Aug 2017, Published online: 21 Sep 2017

References

  • Schatz DG, Ji Y. Recombination centres and the orchestration of V(D)J recombination. Nat Rev Immunol 2011;11:251–263.
  • Klein U, Dalla-Favera R. Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol 2008;8:22–33.
  • Neuberger MS, Milstein C. Somatic hypermutation. Curr Opin Immunol 1995;7:248–254.
  • Honjo T, Kinoshita K, Muramatsu M. Molecular mechanism of class switch recombination: linkage with somatic hypermutation. Annu Rev Immunol 2002;20:165–196.
  • Muramatsu M, Kinoshita K, Fagarasan S, et al. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme figure 1. induced expression of AID in CH12F3-2 cells. Cell 2000;102:553–563.
  • Maul RW, Saribasak H, Martomo SA, et al. Uracil residues dependent on the deaminase AID in immunoglobulin gene variable and switch regions. Nat Immunol 2011;12:70–76.
  • Xu Z, Zan H, Pone EJ, et al. Immunoglobulin class-switch DNA recombination : induction, targeting and beyond. Nat Rev Immunol 2012;12:517–531.
  • Robbiani DF, Nussenzweig MC. Chromosome translocation, B cell lymphoma, and activation-induced cytidine deaminase. Annu Rev Pathol 2013;8:79–103.
  • Kuppers R, Dalla-Favera R. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene 2001;20:5580–5594.
  • Odegard VH, Schatz DG. Targeting of somatic hypermutation. Nat Rev Immunol 2006;6:573–583.
  • Muramatsu M, Sankaranand VS, Anant S, et al. 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;274:18470–18476.
  • Revy P, Muto T, Levy Y, et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 2000;102:565–575.
  • Zahn A, Eranki AK, Patenaude A-M, et al. Activation induced deaminase C-terminal domain links DNA breaks to end protection and repair during class switch recombination. Proc Natl Acad Sci U S A 2014;111:E988–E997.
  • Pham P, Bransteitter R, Petruska J, et al. Processive AID-catalysed cytosine deamination on single-stranded DNA simulates somatic hypermutation. Nature 2003;424:103–107.
  • Larijani M, Petrov AP, Kolenchenko O, et al. AID associates with single-stranded DNA with high affinity and a long complex half-life in a sequence-independent manner. Mol Cell Biol 2007;27:20–30.
  • Bransteitter R, Pham P, Calabrese P, et al. Biochemical analysis of hypermutational targeting by wild type and mutant activation-induced cytidine deaminase. J Biol Chem 2004;279:51612–51621.
  • Goodman MF, Scharff MD, Romesberg FE. AID-initiated purposeful mutations in immunoglobulin genes. Adv Immunol 2007;94:127–155.
  • Brar SS, Sacho EJ, Tessmer I, et al. Activation-induced deaminase, AID, is catalytically active as a monomer on single-stranded DNA. DNA Repair (Amst) 2008;7:77–87.
  • Mondal S, Begum NA, Hu W, et al. Functional requirements of AID's higher order structures and their interaction with RNA-binding proteins. Proc Natl Acad Sci U S A 2016;113:E1545–E1554.
  • Dickerson SK, Market E, Besmer E, et al. AID mediates hypermutation by deaminating single stranded DNA. J Exp Med 2003;5600:1291–1296.
  • Ta V-T, Nagaoka H, Catalan N, et al. AID mutant analyses indicate requirement for class-switch-specific cofactors. Nat Immunol 2003;4:843–848.
  • Chaudhuri J, Basu U, Zarrin A, et al. Evolution of the immunoglobulin heavy chain class switch recombination mechanism. Adv Immunol 2007;94:157–214.
  • Han L, Masani S, Yu K. Overlapping activation-induced cytidine deaminase hotspot motifs in Ig class-switch recombination. Proc Natl Acad Sci U S A 2011;108:11584–11589.
  • Ramiro AR, Stavropoulos P, Jankovic M, et al. Transcription enhances AID-mediated cytidine deamination by exposing single-stranded DNA on the nontemplate strand. Nat Immunol 2003;4:452–456.
  • Robbiani DF, Bunting S, Feldhahn N, et al. AID produces DNA double-strand breaks in non-Ig genes and mature B cell lymphomas with reciprocal chromosome translocations. Mol Cell 2009;36:631–641.
  • Martin A, Scharff MD. Somatic hypermutation of the AID transgene in B and non-B cells. Proc Natl Acad Sci U S A 2002;99:12304–12308.
  • Neuberger MS, Harris RS, Di Noia J, et al. Immunity through DNA deamination. Trends Biochem Sci 2003;28:305–312.
  • Diaz M, Verkoczy LK, Flajnik MF, et al. Decreased frequency of somatic hypermutation and impaired affinity maturation but intact germinal center formation in mice expressing antisense RNA to DNA polymerase zeta. J Immunol 2001;167:327–335.
  • Schenten D, Kracker S, Esposito G, et al. Pol zeta ablation in B cells impairs the germinal center reaction, class switch recombination, DNA break repair, and genome stability. J Exp Med 2009;206:477–490.
  • Zan H, Komori A, Li Z, et al. The translesion DNA polymerase zeta plays a major role in Ig and bcl-6 somatic hypermutation. Immunity 2001;14:643–653.
  • Masuda K, Ouchida R, Li Y, et al. A critical role for REV1 in regulating the induction of C:G transitions and A:T mutations during Ig gene hypermutation. J Immunol 2009;183:1846–1850.
  • Delbos F, De Smet A, Faili A, et al. Contribution of DNA polymerase η to immunoglobulin gene hypermutation in the mouse. J Exp Med 2005;201:1191–1196.
  • Faili A, Aoufouchi S, Weller S, et al. DNA polymerase eta is involved in hypermutation occurring during immunoglobulin class switch recombination. J Exp Med 2004;1265600:265–270.
  • Zeng X, Winter DB, Kasmer C, et al. DNA polymerase eta is an A-T mutator in somatic hypermutation of immunoglobulin variable genes. Nat Immunol 2001;2:537–541.
  • Zeng X, Negrete GA, Kasmer C, et al. Absence of DNA polymerase eta reveals targeting of C mutations on the nontranscribed strand in immunoglobulin switch regions. J Exp Med 2004;199:917–924.
  • Wilson TM, Vaisman A, Martomo SA, et al. MSH2 – MSH6 stimulates DNA polymerase eta, suggesting a role for A : T mutations in antibody genes. J Exp Med 2005;201:637–645.
  • Betz AG, Milstein C, Gonzalez-Fernandez A, et al. Elements regulating somatic hypermutation of an immunoglobulin kappa gene: critical role for the intron enhancer/matrix attachment region. Cell 1994;77:239–248.
  • Peters A, Storb U. Somatic hypermutation of immunoglobulin genes is linked to transcription initiation. Immunity 1996;4:57–65.
  • Kodgire P, Mukkawar P, Ratnam S, et al. Changes in RNA polymerase II progression influence somatic hypermutation of Ig-related genes by AID. J Exp Med 2013;210:1481–1492.
  • Shen HM, Storb U. Activation-induced cytidine deaminase (AID) can target both DNA strands when the DNA is supercoiled. Proc Natl Acad Sci U S A 2004;101:12997–13002.
  • Kodgire P, Mukkawar P, North JA, et al. Nucleosome stability dramatically impacts the targeting of somatic hypermutation. Mol Cell Biol 2012;32:2030–2040.
  • Basu U, Meng FL, Keim C, et al. The RNA exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates. Cell 2011;144:353–363.
  • Manis JP, Tian M, Alt FW. Mechanism and control of class-switch recombination. Trends Immunol 2002;23:31–39.
  • Stavnezer J, Schrader CE. Mismatch repair converts AID-instigated nicks to double-strand breaks for antibody class-switch recombination. Trends Genet 2006;22:23–28.
  • Yu K, Chedin F, Hsieh C-L, et al. R-loops at immunoglobulin class switch regions in the chromosomes of stimulated B cells. Nat. Immunol 2003;4:442–451.
  • Chaudhuri J, Alt FW. Class-switch recombination: interplay of transcription, DNA deamination and DNA repair. Nat Rev Immunol 2004;4:541–552.
  • Reynaud CA, Anquez V, Grimal H, et al. A hyperconversion mechanism generates the chicken light chain preimmune repertoire. Cell 1987;48:379–388.
  • Wysocki LJ, Gefter ML. Gene conversion and the generation of antibody diversity. Annu Rev Biochem 1989;58:509–531.
  • Arakawa H, Hauschild J, Buerstedde J-M. Requirement of the activation-induced deaminase (AID) gene for immunoglobulin gene conversion. Science 2002;295:1301–1306.
  • McCormack WT, Tjoelker LW, Thompson CB. Avian B-cell development: generation of an immunoglobulin repertoire by gene conversion. Annu Rev Immunol 1991;9:219–241.
  • Reynaud CA, Bertocci B, Dahan A, et al. Formation of the chicken B-cell repertoire: ontogenesis, regulation of Ig gene rearrangement, and diversification by gene conversion. Adv Immunol 1994;57:353–378.
  • Di Noia J, Neuberger MS. Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature 2002;419:43–48.
  • Noia JMD, Neuberger MS. Immunoglobulin gene conversion in chicken DT40 cells largely proceeds through an abasic site intermediate generated by excision of the uracil produced by AID-mediated deoxycytidine deamination. Eur J Immunol 2004;34:504–508.
  • Saribasak H, Saribasak NN, Ipek FM, et al. Uracil DNA glycosylase disruption blocks Ig gene conversion and induces transition mutations. J Immunol 2006;176:365–371.
  • Sale JE, Calandrini DM, Takata M, et al. Ablation of XRCC2/3 transforms immunoglobulin V gene conversion into somatic hypermutation. Nature 2001;412:921–926.
  • Arakawa H, Saribasak H, Buerstedde J-M. Activation-induced cytidine deaminase initiates immunoglobulin gene conversion and hypermutation by a common intermediate. PLoS Biol 2004;2:E179.
  • Kohli RM, Abrams SR, Gajula KS, et al. A portable hot spot recognition loop transfers sequence preferences from APOBEC family members to activation-induced cytidine deaminase. J Biol Chem 2009;284:22898–22904.
  • Nabel CS, Lee JW, Wang LC, et al. Nucleic acid determinants for selective deamination of DNA over RNA by activation-induced deaminase. Proc Natl Acad Sci U S A 2013;110:14225–14230.
  • Bransteitter R, Pham P, Scharff MD, et al. Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase. Proc Natl Acad Sci U S A 2003;100:4102–4107.
  • Morgan HD, Dean W, Coker HA, et al. Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues: Implications for epigenetic reprogramming. J Biol Chem 2004;279:52353–52360.
  • Nabel CS, Jia H, Ye Y, et al. AID/APOBEC deaminases disfavor modified cytosines implicated in DNA demethylation. Nat Chem Biol 2012;8:751–758.
  • Larijani M, Frieder D, Sonbuchner TM, et al. Methylation protects cytidines from AID-mediated deamination. Mol Immunol 2005;42:599–604.
  • Kim Y, Tian M. The recruitment of activation induced cytidine deaminase to the immunoglobulin locus by a regulatory element. Mol Immunol 2010;47:1860–1865.
  • Blagodatski A, Batrak V, Schmidl S, et al. A cis-acting diversification activator both necessary and sufficient for AID-mediated hypermutation. PLoS Genet 2009;5:e1000332.
  • Buerstedde JM, Alinikula J, Arakawa H, et al. Targeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences. PLoS Biol 2014;12:e1001831.
  • Mcdonald JJ, Alinikula J, Buerstedde J-M, et al. A critical context-dependent role for E boxes in the targeting of somatic hypermutation. J Immunol 2013;191:1556–1566.
  • Tanaka A, Shen HM, Ratnam S, et al. Attracting AID to targets of somatic hypermutation. J Exp Med 2010;207:405–415.
  • Schoetz U, Cervelli M, Wang Y-D, et al. E2A expression stimulates Ig hypermutation. J Immunol 2006;177:395–400.
  • Kothapalli N, Norton DD, Fugmann SD. Cutting edge: a cis-acting DNA element targets AID-mediated sequence diversification to the chicken Ig light chain gene locus. J Immunol 2008;180:2019–2023.
  • Jeevan-Raj BP, Robert I, Heyer V, et al. Epigenetic tethering of AID to the donor switch region during immunoglobulin class switch recombination. J Exp Med 2011;208:1649–1660.
  • Odegard VH, Kim ST, Anderson SM, et al. Histone modifications associated with somatic hypermutation. Immunity 2005;23:101–110.
  • Wang L, Wuerffel R, Feldman S, et al. S region sequence, RNA polymerase II, and histone modifications create chromatin accessibility during class switch recombination. J Exp Med 2009;206:1817–1830.
  • Seo H, Masuoka M, Murofushi H, et al. Rapid generation of specific antibodies by enhanced homologous recombination. Nat Biotechnol 2005;23:731–735.
  • Lin W, Hashimoto S-I, Seo H, et al. Modulation of immunoglobulin gene conversion frequency and distribution by the histone deacetylase HDAC2 in chicken DT40. Genes Cells 2008;13:255–268.
  • Cummings WJ, Yabuki M, Ordinario EC, et al. Chromatin structure regulates gene conversion. PLoS Biol 2007;5:e246.
  • Maeda K, Singh SK, Eda K, et al. GANP-mediated recruitment of activation-induced cytidine deaminase to cell nuclei and to immunoglobulin variable region DNA. J Biol Chem 2010;285:23945–23953.
  • Wold MS. Replication protein A: a heterotrimeric, single-stranded DNA-binding protein required for eukaryotic DNA metabolism. Annu Rev Biochem 1997;66:61–92.
  • Chaudhuri J, Khuong C, Alt FW. Replication protein A interacts with AID to promote deamination of somatic hypermutation targets. Nature 2004;430:992–998.
  • Vuong BQ, Lee M, Kabir S, et al. Specific recruitment of protein kinase A to the immunoglobulin locus regulates class-switch recombination. Nat Immunol 2009;10:420–426.
  • Pavri R, Gazumyan A, Jankovic M, et al. Activation-induced cytidine deaminase targets DNA at sites of RNA polymerase II stalling by interaction with Spt5. Cell 2010;143:122–133.
  • Kanehiro Y, Todo K, Negishi M, et al. Activation-induced cytidine deaminase (AID)-dependent somatic hypermutation requires a splice isoform of the serine/arginine-rich (SR) protein SRSF1. Proc Natl Acad Sci U S A 2012;109:1216–1221.
  • Xu Z, Fulop Z, Wu G, et al. 14-3-3 adaptor proteins recruit AID to 5′-AGCT-3′-rich switch regions for class switch recombination. Nat Struct Mol Biol 2010;17:1124–1135.
  • Nowak U, Matthews AJ, Zheng S, et al. The splicing regulator PTBP2 interacts with the cytidine deaminase AID and promotes binding of AID to switch-region DNA. Nat Immunol 2011;12:160–166.
  • Zheng S, Vuong BQ, Vaidyanathan B, et al. Non-coding RNA generated following lariat debranching mediates targeting of AID to DNA article non-coding RNA generated following lariat debranching mediates targeting of AID to DNA. Cell 2015;161:762–773.
  • Xu Z, Pone EJ, Al-Qahtani A, et al. Regulation of aicda expression and AID activity: relevance to somatic hypermutation and class switch DNA recombination. Crit Rev Immunol 2007;27:367–397.
  • Dedeoglu F, Horwitz B, Chaudhuri J, et al. Induction of activation-induced cytidine deaminase gene expression by IL-4 and CD40 ligation is dependent on STAT6 and NFkappaB. Int Immunol 2004;16:395–404.
  • Gonda H, Sugai M, Nambu Y, et al. The balance between Pax5 and Id2 activities is the key to AID gene expression. J Exp Med 2003;198:1427–1437.
  • Pauklin S, Sernández I V, Bachmann G, et al. Estrogen directly activates AID transcription and function. J Exp Med 2009;206:99–111.
  • Endo Y, Marusawa H, Kinoshita K, et al. Expression of activation-induced cytidine deaminase in human hepatocytes via NF-kappaB signaling. Oncogene 2007;26:5587–5595.
  • Borchert GM, Holton NW, Larson ED. Repression of human activation induced cytidine deaminase by miR-93 and miR-155. BMC Cancer 2011;11:347.
  • Shaffer AL, Lin KI, Kuo TC, et al. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 2002;17:51–62.
  • Park J, Feng J, Li Y, et al. DNA-dependent protein kinase-mediated phosphorylation of protein kinase B requires a specific recognition sequence in the C-terminal hydrophobic motif. J Biol Chem 2009;284:6169–6174.
  • Basu U, Chaudhuri J, Alpert C, et al. The AID antibody diversification enzyme is regulated by protein kinase A phosphorylation. Nature 2005;438:508–511.
  • McBride KM, Gazumyan A, Woo EM, et al. Regulation of hypermutation by activation-induced cytidine deaminase phosphorylation. Proc Natl Acad Sci U S A 2006;103:8798–8803.
  • McBride KM, Gazumyan A, Woo EM, et al. Regulation of class switch recombination and somatic mutation by AID phosphorylation. J Exp Med 2008;205:2585–2594.
  • Pasqualucci L, Kitaura Y, Gu H, et al. PKA-mediated phosphorylation regulates the function of activation-induced deaminase (AID) in B cells. Proc Natl Acad Sci U S A 2006;103:395–400.
  • King JJ, Larijani M. A novel regulator of activation-induced cytidine deaminase/APOBECs in immunity and cancer: Schrodinger's catalytic pocket. Front Immunol 2017;8:351.
  • King JJ, Manuel CA, Barrett C V, et al. Catalytic pocket inaccessibility of activation-induced cytidine deaminase is a safeguard against excessive mutagenic activity. Structure 2015;23:615–627.
  • Basu U, Franklin A, Alt FW. Post-translational regulation of activation-induced cytidine deaminase. Philos Trans R Soc B Biol Sci 2009;364:667–673.
  • Orthwein A, Patenaude A-M, Affar EB, et al. Regulation of activation-induced deaminase stability and antibody gene diversification by Hsp90. J Exp Med 2010;207:2751–2765.
  • Hasler J, Rada C, Neuberger MS. Cytoplasmic activation-induced cytidine deaminase (AID) exists in stoichiometric complex with translation elongation factor 1 (eEF1A). Proc Natl Acad Sci 2011;108:18366–18371.
  • Pasqualucci L, Guglielmino R, Houldsworth J, et al. Expression of the AID protein in normal and neoplastic B cells. Blood 2004;104:3318–3325.
  • Aoufouchi S, Faili A, Zober C, et al. Proteasomal degradation restricts the nuclear lifespan of AID. J Exp Med 2008;205:1357–1368.
  • Shen HM, Peters A, Baron B, et al. Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science 1998;280:1750–1752.
  • Pasqualucci L, Migliazza A, Fracchiolla N, et al. BCL-6 mutations in normal germinal center B cells: evidence of somatic hypermutation acting outside Ig loci. Proc Natl Acad Sci U S A 1998;95:11816–11821.
  • Gordon MS, Kanegai CM, Doerr JR, et al. Somatic hypermutation of the B cell receptor genes B29 (Igbeta, CD79b) and mb1 (Igalpha, CD79a). Proc Natl Acad Sci U S A 2003;100:4126–4131.
  • Muschen M, Re D, Jungnickel B, et al. Somatic mutation of the CD95 gene in human B cells as a side-effect of the germinal center reaction. J Exp Med 2000;192:1833–1840.
  • Duke JL, Liu M, Yaari G, et al. Multiple transcription factor binding sites predict AID targeting in non-immunoglobulin genes. J Immunol 2013;190:3878–3888.
  • Klein IA, Resch W, Jankovic M, et al. Translocation-capture sequencing reveals the extent and nature of chromosomal rearrangements in B lymphocytes. Cell 2017;147:95–106.
  • Chiarle R, Zhang Y, Frock RL, et al. Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells. Cell 2011;147:107–119.
  • Frock RL, Hu J, Meyers RM, et al. Genome-wide detection of DNA double-stranded breaks induced by engineered nucleases. Nat Biotechnol 2015;33:179–186
  • Meng F-L, Du Z, Federation A, et al. Convergent transcription at intragenic super-enhancers targets AID-initiated genomic instability. Cell 2014;159:1538–1548.
  • Qian J, Wang Q, Dose M, et al. B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity. Cell 2014;159:1524–1537.
  • Stern C. Boveri and the early days of genetics. Nature 1950;166:446.
  • Rowley JD. Chromosome translocations: dangerous liaisons revisited. Nat Rev Cancer 2001;1:245–250
  • Mitelman F, Johansson B, Mertens F. Fusion genes and rearranged genes as a linear function of chromosome aberrations in cancer. Nat Genet 2004;36:331–334.
  • Aten JA, Stap J, Krawczyk PM, et al. Dynamics of DNA double-strand breaks revealed by clustering of damaged chromosome domains. Science 2004;303:92–95.
  • Zhang Y, Gostissa M, Hildebrand DG, et al. The role of mechanistic factors in promoting chromosomal translocations found in lymphoid and other cancers. Adv Immunol 2010;106:93–133.
  • Parada LA, McQueen PG, Misteli T. Tissue-specific spatial organization of genomes. Genome Biol 2004;5:R44.
  • Taub R, Kirsch I, Morton C, et al. Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc Natl Acad Sci U S A 1982;79:7837–7841.
  • Pasqualucci L, Bhagat G, Jankovic M, et al. AID is required for germinal center-derived lymphomagenesis. Nat Genet 2008;40:108–112.
  • Smit LA, Bende RJ, Aten J, et al. Expression of activation-induced cytidine deaminase is confined to B-cell non-Hodgkin's lymphomas of germinal-center phenotype. Cancer Res 2003;63:3894–3898.
  • Pasqualucci L, Neumeister P, Goossens T, et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 2001;412:341–346.
  • Ramiro AR, Jankovic M, Eisenreich T, et al. AID is required for c-myc/IgH chromosome translocations in vivo. Cell 2004;118:431–438.
  • Ramiro AR, Jankovic M, Callen E, et al. Role of genomic instability and p53 in AID-induced c-myc-Igh translocations. Nature 2006;440:105–109.
  • Lohr JG, Stojanov P, Lawrence MS, et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci U S A 2012;109:3879–3884.
  • Robbiani DF, Bothmer A, Callen E, et al. AID Is Required for the Chromosomal Breaks in c-myc that Lead to c-myc/IgH Translocations. Cell 2008;135:1028–1038.
  • Komeno Y, Kitaura J, Watanabe-Okochi N, et al. AID-induced T-lymphoma or B-leukemia/lymphoma in a mouse BMT model. Leukemia 2010;2440:1018–1024.
  • Okazaki I, Kinoshita K, Muramatsu M, et al. The AID enzyme induces class switch recombination in fibroblasts. Nature 2002;416:340–345.
  • Bekerman E, Jeon D, Ardolino M, et al. A role for host activation-induced cytidine deaminase in innate immune defense against KSHV. PLoS Pathog 2013;9:e1003748.
  • Gourzi P, Leonova T, Papavasiliou FN. A role for activation-induced cytidine deaminase in the host response against a transforming retrovirus. Immunity 2006;24:779–786.
  • Kou T, Marusawa H, Kinoshita K, et al. Expression of activation-induced cytidine deaminase in human hepatocytes during hepatocarcinogenesis. Int J Cancer 2007;120:469–476.
  • Gourzi P, Leonova T, Papavasiliou FN. Viral induction of AID is independent of the interferon and the Toll-like receptor signaling pathways but requires NF-κB. J Exp Med 2007;204:259–265.
  • Okazaki I-M, Hiai H, Kakazu N, et al. Constitutive expression of AID leads to tumorigenesis. J Exp Med 2003;197:1173–1181.
  • Komori J, Marusawa H, Machimoto T, et al. Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma. Hepatology 2008;47:888–896.
  • Endo Y, Marusawa H, Kou T, et al. Activation-induced cytidine deaminase links between inflammation and the development of colitis-associated colorectal cancers. Gastroenterology 2008;135:889–898.
  • Ben-Neriah Y, Karin M. Inflammation meets cancer, with NF-kappaB as the matchmaker. Nat. Immunol 2011;12:715–723.
  • Matsumoto Y, Marusawa H, Kinoshita K, et al. Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. Nat Med 2007;13:470–476.
  • Revy P, Muto T, Levy Y, et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the hyper-IgM syndrome (HIGM2). Cell 2000;102:565–575.
  • Durandy A, Cantaert T, Kracker S, et al. Potential roles of Activation-Induced cytidine Deaminase in promotion or prevention of autoimmunity in humans. Autoimmunity 2013;46:148–156.
  • White CA, Seth Hawkins J, Pone EJ, et al. AID dysregulation in lupus-prone MRL/Faslpr/lpr mice increases class switch DNA recombination and promotes interchromosomal c-Myc/IgH loci translocations: Modulation by HoxC4. Autoimmunity 2011;44:585–598.
  • Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031–1037.
  • Mrózek K, Harper DP, Aplan PD. Cytogenetics and molecular genetics of acute lymphoblastic leukemia. Hematol Oncol Clin North Am 2009;23:991–1010.
  • Klemm L, Duy C, Iacobucci I, et al. The B cell mutator AID promotes B lymphoid blast crisis and drug resistance in chronic myeloid leukemia. Cancer Cell 2009;16:232–245.
  • Gruber TA, Chang MS, Sposto R, et al. Activation-induced cytidine deaminase accelerates clonal evolution in BCR-ABL1-driven B-cell lineage acute lymphoblastic leukemia. Cancer Res 2010;70:7411–7420.
  • Kawamura K, Wada A, Wang J-Y, et al. Expression of activation-induced cytidine deaminase is associated with a poor prognosis of diffuse large B cell lymphoma patients treated with CHOP-based chemotherapy. J Cancer Res Clin Oncol 2015;142:27–36.
  • Shikata H, Yakushijin Y, Matsushita N, et al. Role of activation-induced cytidine deaminase in the progression of follicular lymphoma. Cancer Sci 2012;103:415–421.
  • Aguilera NS, Auerbach A, Barekman CL, et al. Activation-induced cytidine deaminase expression in diffuse large B-cell lymphoma with a paracortical growth pattern a lymphoma of possible interfollicular large B-cell origin. Arch Pathol Lab Med 2010;134:449–456.
  • Deutsch AJA, Frü Hwirth M, Aigelsreiter A, et al. Primary cutaneous marginal zone B-cell lymphomas are targeted by aberrant somatic hypermutation. J Invest Dermatol 2009;129:476–479.
  • Feldhahn N, Henke N, Melchior K, et al. Activation-induced cytidine deaminase acts as a mutator in BCR-ABL1-transformed acute lymphoblastic leukemia cells. J Exp Med 2007;204:1157–1166.
  • Iacobucci I, Lonetti A, Messa F, et al. Different isoforms of the B-cell mutator activation-induced cytidine deaminase are aberrantly expressed in BCR-ABL1-positive acute lymphoblastic leukemia patients. Leukemia 2009;24:66–73.
  • Wu X, Darce JR, Chang SK, et al. Alternative splicing regulates activation-induced cytidine deaminase (AID): implications for suppression of AID mutagenic activity in normal and malignant B cells. Blood 2008;112:4675–4682.
  • Brauninger A, Spieker T, Mottok A, et al. Epstein-Barr virus (EBV)-positive lymphoproliferations in post-transplant patients show immunoglobulin V gene mutation patterns suggesting interference of EBV with normal B cell differentiation processes. Eur J Immunol 2003;33:1593–1602.
  • Deutsch AJA, Aigelsreiter A, Staber PB, et al. Brief report MALT lymphoma and extranodal diffuse large B-cell lymphoma are targeted by aberrant somatic hypermutation. Blood 2007;109:3500–3504.
  • Thaunat O, Nicoletti A. Comment on “activation-induced cytidine deaminase expression in follicular dendritic cell networks and interfollicular large B cells supports functionality of ectopic lymphoid neogenesis in autoimmune sialoadenitis and MALT lymphoma in sjogren's syndrome.” J Immunol 2008;180:2007–2008.
  • Robbiani DF, Deroubaix S, Feldhahn N, et al. Plasmodium infection promotes genomic instability and AID-dependent B cell lymphoma. Cell 2015;162:727–737.
  • Takai A, Toyoshima T, Uemura M, et al. A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations. Oncogene 2008;28:469–478.
  • Endo Y, Marusawa H, Chiba T. Involvement of activation-induced cytidine deaminase in the development of colitis-associated colorectal cancers. J Gastroenterol 2011;46:6–10.
  • Sapoznik S, Bahar-Shany K, Brand H, et al. Activation-induced cytidine deaminase links ovulation-induced inflammation and serous carcinogenesis. Neoplasia 2016;18:90–99.
  • Sawai Y, Kodama Y, Shimizu T, et al. Activation-induced cytidine deaminase contributes to pancreatic tumorigenesis by inducing tumor-related gene mutations. Cancer Res 2015;75:3292–3301.
  • Babbage G, Ottensmeier CH, Blaydes J, et al. Immunoglobulin heavy chain locus events and expression of activation-induced cytidine deaminase in epithelial breast cancer cell lines. Cancer Res 2006;66:3996–4000.
  • Shinmura K, Igarashi H, Goto M, et al. Aberrant expression and mutation-inducing activity of AID in human lung cancer. Ann Surg Oncol 2011;18:2084–2092.
  • Nakanishi Y, Kondo S, Wakisaka N, et al. Role of activation-induced cytidine deaminase in the development of oral squamous cell carcinoma. PLoS One 2013;8:e62066.
  • Sun Y, Peng I, Senger K, et al. Critical role of activation induced cytidine deaminase in experimental autoimmune encephalomyelitis. Autoimmunity 2013;46:157–167.
  • Xu X, Hsu H, Chen J, et al. Increased expression of activation-induced cytidine deaminase is associated with Anti-CCP and rheumatoid factor in rheumatoid arthritis. Scand J Immunol 2009;70:309–316.

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