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Prepublished online as a Blood First Edition Paper on January 9, 2003; DOI 10.1182/blood-2002-10-3175. This Article Abstract Full Text (PDF) All Versions of this Article: 2002-10-3175v1 101/10/4029    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Oppezzo, P. Articles by Dighiero, G. Search for Related Content PubMed PubMed Citation Articles by Oppezzo, P. Articles by Dighiero, G. Related Collections Immunobiology Neoplasia Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 May 2003, Vol. 101, No. 10, pp. 4029-4032 IMMUNOBIOLOGY Brief report Chronic lymphocytic leukemia B cells expressing AID display dissociation between class switch recombination and somatic hypermutation Pablo Oppezzo, Françoise Vuillier, Yuri Vasconcelos, Gérard Dumas, Christian Magnac, Béatrice Payelle-Brogard, Otto Pritsch, and Guillaume Dighiero From the Unité d'Immuno-hématologie et d'Immunopathologie, Institut Pasteur, Paris, France; Disciplina de Hematologia e Hemoterapia, Universidade Federal de Sao Paulo, Brazil; and Departamento de Bioquímica, Facultad de Medicina de Montevideo, Uruguay.     Abstract Top Abstract Introduction Study design Results and discussion References In B cells, somatic hypermutation (SHM) and class switch recombination (CSR) depend on the activation-induced cytidine deaminase (AID) gene product, although the precise mode of action of AID remains unknown. Because some chronic lymphocytic leukemia (CLL) B cells can undergo CSR without SHM, it constitutes a useful model to dissect AID function. In this work, we have studied AID expression, the presence of mutations in the preswitch µ DNA region, CSR, and the SHM in 65 CLL patients. Our results demonstrate that unmutated CLL B cells can constitutively express AID and that AID expression is associated with the presence of mutations in the preswitch region and in clonally related isotype-switched transcripts. They also demonstrate that in CLL without constitutive AID expression, AID induction on stimulation results in preswitch mutations and the CSR process. Our results show a dissociation between SHM and CSR in CLL and suggest that, in this disease, AID would require additional help for carrying out the SHM process. (Blood. 2003;101:4029-4032) © 2003 by The American Society of Hematology.     Introduction Top Abstract Introduction Study design Results and discussion References After gene rearrangement, immunoglobulin (Ig) variable genes are diversified by somatic hypermutation (SHM), whereas the effector function of the constant domain is modified by class switch recombination (CSR). These processes depend on activation-induced cytidine deaminase (AID), a putative RNA-editing enzyme expressed in B cells from secondary lymphoid organs on CD40 ligand (CD40L) stimulation.1 Given that the absence of AID expression in one form of the hyper-IgM syndrome in humans2 and in AID-targeted mice abolishes CSR and SHM, this protein is thought to play a major role in both processes.3 Fifty percent of patients with chronic lymphocytic leukemia (CLL) display mutated VH genes.4 The mutational profile of immunoglobulin genes represents an important prognostic factor5,6 because patients expressing unmutated VH genes exhibit poor prognoses. In addition, previous reports7-9 have demonstrated that CSR frequently occurs in CLL and predominates in unmutated B-cell CLLs (B-CLLs). In this work, we have examined the expression of AID transcripts, SHM, and CSR in 65 patients with CLL expressing either unmutated (33 of 65) or mutated (32 of 65) VH genes. Our results show that patients with unmutated B-CLL can constitutively express AID transcripts. This fact is associated with the presence of mutations in the preswitch µ DNA region and with an active CSR, but it is not related to the SHM process. Additionally, in patients with mutated CLL without constitutive AID expression, AID induction on stimulation results in preswitch mutations and the CSR process.     Study design Top Abstract Introduction Study design Results and discussion References Healthy and CLL samples Blood was collected from 4 healthy controls and 65 typical CLL patients from Hôtel-Dieu, Pitié-Salpêtrière, and Pasteur hospitals (Paris, France), Sao Paulo and Servidor Publico Estadual hospitals (Sao Paulo, Brazil), and Hospital Maciel (Montevideo, Uruguay). B cells were purified through negative depletion by using RosetteSep antibody cocktail (StemCell Technologies, Vancouver, BC, Canada) and were stimulated in vitro for 5 days with 1 µg/mL recombinant soluble CD40L (Immunex, Seattle, WA) and 1000 U/mL interleukin (IL)-4 (PharMingen, San Diego, CA). Analysis of AID transcripts Polymerase chain reaction (PCR) amplification of CLL cDNA was carried out as described previously,2 and a semiquantitative protocol for AID expression was performed. Briefly, cDNA obtained from 5 × 106 B cells was amplified by 20 cycles of PCR using AID2 and GAPDH (glyceraldehyde-3-phosphate dehydrogenase)10 primers. The fragments obtained were transferred and hybridized with specific AID and GAPDH -[32P] dCTP (deoxycytidine-5'-triphosphate)-labeled probes. Analysis of CSR process PCR amplification of different isotype transcripts was performed as described by Oppezzo et al.9 Circle isotype-specific (I-C) transcripts, termed circle transcripts (CTs), were analyzed by PCR with primers I- (forward) and C-µ (reverse), as described by Kinoshita et al.11 Mutation analysis of VH and preswitch regions Sequences of VH genes were determined as previously described.12 Mutations in the Iµ/Sµ region were studied by PCR using Taq High Fidelity polymerase (Roche Diagnostics, Mannheim, Germany) with the following primers: (A) 5'-GGC TGA CCG AAA CTG AAA AGG C-3'; and (D) 5'-GAA AGC TGG ATG AGT GTC ATG GCC-3'.     Results and discussion Top Abstract Introduction Study design Results and discussion References CLL B cells can constitutively express AID transcripts, which predominate among unmutated cases and are associated with the expression of additional clonally related transcripts Unmutated cases predominated among aggressive forms of CLL (25 of 34, stages B and C) whereas mutated cases predominated in stage A (23 of 31). By using a stringent semiquantitative reverse transcription (RT)-PCR, we could substantiate constitutive AID expression in 10 of 65 patients, which might have accounted for a lower incidence when compared with another series13 (Figure 1A). Interestingly, all these patients expressed unmutated rearranged VH genes and displayed either advanced disease (stage B in 4) or progressive disease (stage A in 6). As shown in Figure 1B, different AID transcripts were amplified by RT-PCR, corresponding, respectively, to the complete sequence of AID transcript previously reported by Revy et al,2 a fragment displaying a 10-amino acid deletion in the initial portion of exon 4, and a fragment with a 51-amino acid deletion including exons 4 and 5. Different AID-splicing variants have also been reported by Noguchi et al.14 View larger version (26K): [in this window] [in a new window]   Figure 1. Expression of AID RNA transcripts in CLL and their relation in CSR and SHM process. (A) Semiquantitative AID expression. The expression of AID transcripts was monitored by semiquantitative RT-PCR using AID and GAPDH-specific primers in the same RT-PCR tube reaction. Representative amplification for healthy B cells (00) and either unmutated (01 and 03) or mutated (05 and 07) B-CLLs are shown. Amounts of AID transcripts were determined by normalization with internal GAPDH expression. Relative units corresponding to AID and GAPDH transcript amplification levels were quantified by Quant software (Molecular Dynamics). (B) Presence of different AID RNA transcripts. Normal cDNA (00) and CLL cDNA (01) were amplified and migrated. Three different RNA forms of the AID gene were found (1, 2, 3). The figure depicts a schematic sequence of AID mRNA previously reported by Schroeder et al,4 corresponding to 198 amino acids. The other 2 variants are spliced forms, one consisting of 618 base pair (bp) with an open-reading frame containing a deletion of 10 amino acids and the other consisting of 495 bp containing a complete deletion of exons 4 and 5 (51 amino acids). Deletions are depicted as unfilled rectangles. (C) Clonal isotype switch transcripts. mRNA transcript amplifications with tumor-related VH primers in 5' and Cµ, C, C, and C in 3' from patients 1 and 3 with unmutated and patients 5 and 7 with mutated disease. Patient 1 expresses µ, , , and  transcripts, and patient 3 expresses µ, , and  tumorally related transcripts, whereas patients 5 and 7 only express µ and  transcripts related to the tumoral clone. The smearlike amplification observed for patient 7 corresponds to a polyclonal amplification of different  transcripts as confirmed by sequence. After stimulation patient 5 expressed a tumorally related  transcript, and patient 7 acquired tumorally related  and  transcripts. (D) Distributions of mutations in the Iµ/Sµ region. A 1625-bp genomic fragment between the enhancer and the Sµ switch core was amplified with primers A and D for 4 healthy controls and 7 patients with CLL (Table 1). Closed and open arrows indicate point mutations (30 in the 3' subregion, 9 in the 5' subregion). In addition, 4 deletions in the 3' subregion, depicted as rectangles, were observed. Open arrows illustrate where repeated mutations took place. Primers B (5'-TGC CTG TCT CTT ACC ATG TCG GG-3') and C (5'-GAC ATG GTA AGA GAC AGG CAG CCG-3') were used as internal primers for sequencing reaction. Given that in all cases 3 independent sequences obtained from different PCRs with a high-fidelity Taq DNA polymerase (106 expected rate mutation) were carried out, Taq infidelity should play a minor, if any, role in the appearance of mutations. The expression of constitutive AID transcripts in 10 unmutated patients led us to examine the CSR process by analysis of clonal isotype switch transcripts and the presence of -CTs as recently reported in CLL by Cerutti et al.15 Seven of these 10 CLLs expressed µ, , , and  transcripts (Figure 1C), which were substantiated to display VH sequences identical to those expressed by the tumoral clone (data not shown). In addition, -CTs were observed in all these unmutated patients, indicating that the initiation of a CSR process11 is accounted for in these B-CLLs (data not shown). AID expression enables CLL-B cells to carry out CSR somatic-like mutations but not SHM To further investigate the dissociation between SHM and CSR in B-CLLs cells, taking into account that upon stimulation in the conditions that induce CSR, AID induction is associated with hypermutation in the Sµ region under the conditions that induce CSR.16 We have studied B cells from 4 healthy donors and 7 patients with CLL (4 unmutated and 3 mutated) before and after stimulation with CD40L + IL-4 and have considered AID expression by semiquantitative RT-PCR and CSR by searching of clonally related isotype variants, CTs, and somatic-like mutations in the preswitch µ DNA region. Figure 1D depicts the schematic amplified sequence of the preswitch region. Consistent with previous findings,2 CD40L + IL-4 stimulation induced the expression of AID transcripts (Figure 1A). After the exclusion of well-known polymorphisms, comparison of the sequences before and after stimulation demonstrated that AID induction was associated with a significant mutation rate (3 × 103) in the preswitch region. In agreement with previous reports,16 a high number of these mutations were accumulated mainly in the 3' region of the amplified fragment (Figure 1D), indicating that a hypermutation process took place in the human Ig preswitch region and that this process was AID dependent. CLL patients 1, 2, 3, and 4 without SHM in VH genes were found to constitutively express AID, clonally related isotype variants, and a high rate of mutations in the preswitch region (Table 1). In addition, neither AID transcripts nor additional tumorally related transcripts were observed in CLL patients 5, 6, and 7 with VH mutations (Table 1) before CD40L + IL-4 stimulation. However, AID transcripts and clonally related isotype variants were found for patients 5 and 7 on stimulation (Figure 1C).                                View this table: [in this window] [in a new window]   Table 1. Implication of AID expression in mutational profile of Iµ/Sµ region, CSR, and SHM AID may act as an RNA-editing enzyme involved in the edition of endonucleases responsible for CSR and SHM,3,17 either by editing a single substrate or separate pre-mRNAs for CSR and SHM.18 On the other hand, recent evidence suggests that AID triggers antibody diversification by the deamination of nucleotides within the immunoglobulin locus itself.19,20 Different results suggest that AID is sufficient to activate the SHM and CSR processes and that its activity does not depend on other centroblast-specific factors.19,21,22 Our results show, however, that AID expression is associated with CSR but not with SHM. This dissociation observed in CLL, combined with previous work in a mouse model16 and in the BL2 Burkitt cell line,23 favors the view that AID may act differentially on CSR and SHM. In agreement with recent work24 demonstrating that with strong stimulation through the B-cell receptor (BCR), patients with CLL are able to acquire somatic mutations, our results suggest that AID is necessary but not sufficient for the SHM process, and that additional levels of regulation could be required for the efficient function of this protein.25     Acknowledgments We thank Drs Mirta Giordano, Michelle Goodhardt, and Frédéric Davi for review and discussion of this manuscript.     Footnotes Submitted October 21, 2002; accepted December 23, 2002. Prepublished online as Blood First Edition Paper, January 9, 2003; DOI 10.1182/blood-2002-10-3175. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: G. Dighiero, Unité d'Immuno-Hématologie et d'Immunopathologie, Institut Pasteur, 28 Rue Docteur Roux, 75015 Paris, France; e-mail: dighiero{at}pasteur.fr.     References Top Abstract Introduction Study design Results and discussion References 1. 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[Abstract/Free Full Text]. 2. 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[Medline] [Order article via Infotrieve]. 3. Honjo T, Kinoshita K, Muramatsu M. Molecular mechanism of class switch recombination: linkage with somatic hypermutation. Annu Rev Immunol. 2002;20:165-196[CrossRef][Medline] [Order article via Infotrieve]. 4. Schroeder HW Jr, Dighiero G. The pathogenesis of chronic lymphocytic leukemia: analysis of the antibody repertoire. Immunol Today. 1994;15:288-294[CrossRef][Medline] [Order article via Infotrieve]. 5. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94:1848-1854[Abstract/Free Full Text]. 6. Damle RN, Wasil T, Fais F. et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999;94:1840-1847[Abstract/Free Full Text]. 7. Fais F, Sellars B, Ghiotto F, et al. Examples of in vivo isotype class switching in IgM+ chronic lymphocytic leukemia B cells. J Clin Invest. 1996;98:1659-1666[Abstract/Free Full Text]. 8. Efremov DG, Ivanovski M, Batista FD, Pozzato G, Burrone OR. IgM-producing chronic lymphocytic leukemia cells undergo immunoglobulin isotype-switching without acquiring somatic mutations. J Clin Invest. 1996;98:290-298[Abstract/Free Full Text]. 9. Oppezzo P, Magnac C, Bianchi S, et al. Do CLL B cells correspond to naive or memory B-lymphocytes? evidence for an active Ig switch unrelated to phenotype expression and Ig mutational pattern in B-CLL cells. Leukemia. 2002;16:2438-2446[CrossRef][Medline] [Order article via Infotrieve]. 10. Lee CG, Kinoshita K, Arudchandran A, Cerritelli SM, Crouch RJ, Honjo T. Quantitative regulation of class switch recombination by switch region transcription. J Exp Med. 2001;194:365-374[Abstract/Free Full Text]. 11. Kinoshita K, Harigai M, Fagarasan S, Muramatsu M, Honjo T. A hallmark of active class switch recombination: transcripts directed by I promoters on looped-out circular DNAs. Proc Natl Acad Sci U S A. 2001;98:12620-12623[Abstract/Free Full Text]. 12. Pritsch O, Magnac C, Dumas G, Egile C, Dighiero G. V gene usage by seven hybrids derived from CD5+ B-cell chronic lymphocytic leukemia and displaying autoantibody activity. Blood. 1993;82:3103-3112[Abstract]. 13. Albesiano E, Damle R, Steven L, et al. Activation-induced cytidine deaminase (AID) expression in B-CLL [abstract]. Blood. 2002;100:99a. 14. Noguchi E, Shibasaki M, Inudou M, et al. Association between a new polymorphism in the activation-induced cytidine deaminase gene and atopic asthma and the regulation of total serum IgE levels. J Allergy Clin Immunol. 2001;108:382-386[CrossRef][Medline] [Order article via Infotrieve]. 15. Cerutti A, Zan H, Kim E, et al. Ongoing in vivo immunoglobulin class switch DNA recombination in chronic lymphocytic leukemia B cells. J Immunol. 2002;169:6594-6603[Abstract/Free Full Text]. 16. Nagaoka H, Muramatsu M, Yamamura N, Kinoshita K, Honjo T. Activation-induced deaminase (AID)-directed hypermutation in the immunoglobulin Smu region: implication of AID involvement in a common step of class switch recombination and somatic hypermutation. J Exp Med. 2002;195:529-534[Abstract/Free Full Text]. 17. Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell. 2000;102:553-563[Medline] [Order article via Infotrieve]. 18. Papavasiliou FN, Schatz DG. Somatic hypermutation of immunoglobulin genes: merging mechanisms for genetic diversity. Cell. 2002;109(suppl):S35-S44[Medline] [Order article via Infotrieve]. 19. Petersen-Mahrt SK, Harris RS, Neuberger MS. AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature. 2002;418:99-103[CrossRef][Medline] [Order article via Infotrieve]. 20. Di Noia J., Neuberger S. Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature [advance online publication]. 2002;July 31:1-6. 21. Martin A, Bardwell PD, Woo CJ, Fan M, Shulman MJ, Scharff MD. Activation-induced cytidine deaminase turns on somatic hypermutation in hybridomas. Nature. 2002;415:802-806[Medline] [Order article via Infotrieve]. 22. Yoshikawa K, Okazaki IM, Eto T, et al. AID enzyme-induced hypermutation in an actively transcribed gene in fibroblasts. Science. 2002;296:2033-2036[Abstract/Free Full Text]. 23. Faili A, Aoufouchi S, Gueranger Q, et al. AID-dependent somatic hypermutation occurs as a DNA single-strand event in the BL2 cell line [abstract]. Nat Immunol. 2002;29:29. 24. Gurrieri C, McGuire P, Zan H, et al. Chronic lymphocytic leukemia B cells can undergo somatic hypermutation and intraclonal immunoglobulin V(H)DJ(H) gene diversification. J Exp Med. 2002;196:629-639[Abstract/Free Full Text]. 25. Honjo T. 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[Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) All Versions of this Article: 2002-10-3175v1 101/10/4029    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Oppezzo, P. Articles by Dighiero, G. Search for Related Content PubMed PubMed Citation Articles by Oppezzo, P. Articles by Dighiero, G. Related Collections Immunobiology Neoplasia Brief Reports Social Bookmarking                   What's this?

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