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Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 March 2001, Vol. 97, No. 6, pp. 1892-1894 CORRESPONDENCE To the editor: CD38 expression is a poor predictor for VH gene mutational status and prognosis in chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) has traditionally been viewed as a neoplastic proliferation of naive B cells of the mantle zone, but this view is now changing, with reports of somatically mutated immunoglobulin (Ig) variable heavy chain (VH) genes in CLL.1,2 Recently, Hamblin et al1 and Damle et al2 have independently demonstrated that CLL comprises 2 subsets with either mutated or unmutated VH genes. The mutated CLL cases had a more favorable prognosis and required less treatment than the unmutated cases. Both studies postulated that CLL cells might originate from 2 different stages of B-cell development, ie, pre- or post-GC (germinal center) B cells. Moreover, Damle et al found a strong correlation between VH gene mutational status and CD38 expression in CLL, where unmutated cases displayed a higher percentage of CD38+ cells (> 30%) than mutated cases (< 30%).1 Damle et al proposed that both VH gene mutational status and CD38 expression could be used as novel prognostic indicators of clinical outcome in CLL. But in a follow-up study by Hamblin et al,3 they could not confirm any association between Ig mutational status and CD38 expression, although a significantly poorer prognosis was observed among the cases with more than 30% CD38+.3 We have analyzed the VH gene mutational status in 107 B-cell CLL (B-CLL) cases, and moreover, we have evaluated the CD38 expression in 48 of these cases to further clarify the correlation between VH gene mutations and CD38 expression. DNA was extracted mainly from lymph nodes and peripheral blood lymphocytes, and VH gene family-specific polymerase chain reaction (PCR) amplification was performed as previously described.4 The majority of samples were sequenced directly using an automated DNA sequencer (ABI 377, Applied Biosystems, Foster City, CA), and the nucleotide sequences were compared to the BLASTN and V-BASE databases. Less than 98% homology to the corresponding germline gene was defined as a mutated VH gene. In a subset of cases, the surface expression of CD38 was evaluated using 2-color flow cytometry and direct conjugate antibodies (anti-CD19-FITC/anti-CD38-PE). We amplified and sequenced 115 clonal Ig rearrangements in 107 B-CLL cases, where 8 cases displayed 2 different Ig rearrangements within the same tumor sample. In accordance with previous studies, overexpression of the VH1 family (31.3%) and, particularly, the VH1-69 gene (16.5% of all rearrangements detected) was found.1,2,4 Forty-eight cases (44.9%) showed mutated VH genes, whereas 59 cases (55.1%) were unmutated. The VH1-69 gene was exclusively expressed in unmutated cases with a high frequency (28% of unmutated VH genes), and the VH3-21 gene was mainly found expressed in the mutated cases (19% of mutated, as opposed to 3% of unmutated, VH genes). Interestingly, 1 of 8 cases displaying 2 VH rearrangements showed discrepancy in the mutation pattern between the 2 VH genes (94.4% versus 100% homology). Analysis of distribution of replacement (R) and silent mutations within the complementarity determining regions (CDRs) and framework regions (FRs) using the algorithm of Chang and Casali5 showed that 4 cases had significant clustering of R mutations in the CDRs and scarcity of R mutations in the FRs. In addition, 3 cases displayed clustering of R mutations within the CDRs, and in 6 cases evidence for preservation of the FRs was found. Thus in contrast to previous reports, only a minority of our CLL cases showed evidence of antigen-driven selection. The CD38 expression was analyzed in a subset of 48 CLL patients, where 13 cases displayed more than 30% CD38+ cells (27.1%) and 35 cases, less than 30% CD38+ cells (72.9%). Thirty cases had unmutated VH genes, and 18 were mutated. The unmutated cases demonstrated a variety of CD38 values (0-83%), 11 of which had more than 30% CD38+ cells (Figure 1). The majority of mutated cases showed a low level of CD38 expression, but 2 cases displayed more than 30% of CD38+ cells. Thus 11 of 13 cases with more than 30% CD38+ cells had unmutated VH genes. View larger version (9K): [in this window] [in a new window]   Figure 1. Percentage of CD38+ cells among B-CLL cases with unmutated and mutated VH genes. Preliminary survival analysis was performed in 44 of these cases with a median follow-up of 88 months (range, 24-468). All patients but one were dead at the time of analysis. Median age was 61 years at diagnosis, and there was no significant age difference concerning either CD38 status or VH gene mutational status. Kaplan-Meyer survival analysis with log-rank test was performed, and no significant difference in survival regarding CD38 status was observed in 34 CD38and 10 CD38+ cases (P = .29). But in 26 cases with unmutated VH genes, survival was significantly inferior compared to the 18 mutated cases (P = .0023). Hence, the prognostic impact of VH gene mutations in CLL was confirmed by our data. In agreement with Damle et al,1 a correlation was found between unmutated VH genes and high level of CD38 expression. But a low level of CD38 expression could not predict whether the VH genes were unmutated or mutated. Moreover, we could not find any prognostic significance analyzing CD38 expression in our CLL cases. We therefore conclude that CD38 expression cannot be used as a surrogate marker for VH gene mutational status in CLL. Ulf Thunberg and Anna Johnson Department of Oncology, Radiology, and Clinical Immunology Uppsala University Uppsala, Sweden Göran Roos Department of Medical Biosciences, Pathology Umeå University Umeå, Sweden Ingrid Thörn, Gerard Tobin, Jan Sällström, Christer Sundström, and Richard Rosenquist Department of Genetics and Pathology Uppsala University Uppsala, Sweden References 1. 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]. 2. Hamblin TJ, Davies Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94:1848-1854[Abstract/Free Full Text]. 3. Hamblin TJ, Orchard JA, Gardiner A, Oscier DG, Davis Z, Stevenson FK. Immunoglobulin V genes and CD38 expression in CLL [letter]. Blood. 2000;95:2455-2456[Free Full Text]. 4. Rosenquist R, Lindström A, Holmberg D, Lindh J, Roos G. VH gene family utilization in different B-cell lymphoma subgroups. Eur J Haematol. 1999;62:123-128[Medline] [Order article via Infotrieve]. 5. Chang B, Casali P. The CDR1 sequences of a major proportion of human germline Ig VH genes are inherently susceptible to amino acid replacement. Immunol Today. 1994;15:367-373[CrossRef][Medline] [Order article via Infotrieve]. Response: Immunoglobulin V genes and CD38 expression analysis in B-cell chronic lymphocytic leukemia B-cell chronic lymphocytic leukemia (B-CLL) cases can be divided into 2 subgroups based on the presence or absence of significant numbers of mutations in the variable (V) region of the immunoglobulin (Ig) genes utilized by the malignant cells. This idea was first suggested by a retrospective analysis of the available Ig V gene sequences1 and was definitively demonstrated by a study of a large cohort of randomly chosen B-CLL patients by Fais et al.2 Since then, other groups3 have confirmed this observation, and it is now accepted that at least 50% of B-CLL cases express mutated Ig V genes. This finding became especially important when it was recognized that a highly significant correlation existed between the clinical course of B-CLL patients and the presence or absence of Ig V somatic mutations.3,4 Specifically, cases expressing unmutated V genes have a worse clinical course in terms of overall survival, requirement for treatment, and progression to more advanced stages than those cases expressing mutated V genes.3-5 Moreover, Damle et al4 showed that the expression of surface membrane CD38 by more than 30% of B-CLL cells was another independent indicator of poorer prognosis as measured by overall survival and requirement for treatment. Another component of this study was the observation that, in most of the cases analyzed, an inverse correlation existed between CD38 expression and presence of Ig V mutations. This latter finding suggested that these 2 markers usually identified the same cases (accuracy 92% in Damle et al4 and 90% in a later communication6). The notion that CD38 expression may be used as a prognostic marker has been reinforced in Hamblin et al,7 showing that CD38 surface expression was even a better marker of poor prognosis than unmutated Ig V genes. But these authors did not find significant association between CD38 expression and Ig V gene status, although their technical approach to the issue differed considerably from that of Damle et al.6,7 Thunberg et al show that, although the Ig V region sequence represents a reliable prognostic marker, this may not be the case for CD38 expression as assessed in a subset (n = 44) of the cohort of patients analyzed for V gene mutations (n = 107). Moreover, in contrast with Damle et al's data,4 the expression of low levels of CD38 (< 30%) seems to distribute independently of Ig V gene status. Most striking are the data that CD38 expression and poor outcome do not correlate,4 since this observation has been corroborated in an independent study of another well-characterized B-CLL cohort.7 Unfortunately, some technical details are not reported in Thunberg et al's letter, and therefore the causes for the discrepancies are matters of speculation. One finding, however, is immediately apparent and clearly contrasts with the observations of other groups: the percentage of cases falling within the CD38+ group is below the expected value. Thus, 13 of 48 patients were classified as CD38+ (27%), whereas the percentage was 47% in Damle et al4 and 44% in Hamblin et al.7 In addition, in many of the cases investigated by Thunberg et al, lymph nodes, rather peripheral blood cells, were studied. So far, to our knowledge no detailed analysis on potential differences of surface phenotypes has been carried out between cells derived from different sources. Furthermore, the immunofluorescent methodology used by Thunberg et al may be less precise since a double-staining approach was employed (compared to the triple staining procedure reported previously by our groups4,6). In addition, no information is provided on the CD38 monoclonal antibody employed. As a final note, we would like to add 2 considerations about Ig V gene analyses. In Damle et al,4 not only the VH but also VL genes were analyzed in each case. Because about 5% of B-CLL cells may have mutations restricted to the VL genes (Damle et al4 and our unpublished observations, 2000), this may be a reason for the discrepancy between our and their results. In addition, in our study that first identified the 2 B-CLL subgroups based on V gene mutation differences,2,4 care was taken to exclude cases that express more than one VH or VL gene (ie, cases that lack allelic exclusion8). This was done because such double expressers can differ in the mutation status of the 2 alleles, thereby making it difficult to decide into which subgroup to assign these cases. This approach has not been followed by Thunberg et al. In our hands6 CD38 expression still remains a reliable prognostic marker that more often than not correlates with Ig V gene mutation status. We hope that future comparisons of this issue will employ similar technological approaches (3-color immunofluorescence using comparable monoclonal antibodies) in B-CLL cases that have been studied at similar molecular levels (VH and VL gene sequence analyses in cases that maintain allelic exclusion). This will permit the investigative community to understand more precisely the degree to which CD38 expression and Ig V gene mutation status independently predict clinical course and the frequency at which they identify the same B-CLL cases. Franco Fais and Fabio Ghiotto Dipartimento di Medicina Sperimentale Sezione di Anatomia Umana, Università di Genova Genova, Italy Rajendra Damle, Tarun Wasil, and Nicholas Chiorazzi Departments of Medicine North Shore University Hospital and New York University School of Medicine Manhasset, New York Simona Zupo Istituto Nazionale per la Ricerca sul Cancro Università di Genova Genova, Italy Manlio Ferrarini Istituto Nazionale per la Ricerca sul Cancro Dipartimento di Oncologia Clinica e Sperimentale Università di Genova Genova, Italy References 1. Schroeder HJ, 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]. 2. Fais F, Ghiotto F, Hashimoto S, et al. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J Clin Invest. 1998;102:1515-1525[Medline] [Order article via Infotrieve]. 3. 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. 4. 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. 5. Maloum K, Davi F, Merle-Béral H, et al. Expression of unmutated VH genes is a detrimental prognostic factor in chronic lymphocytic leukemia. Blood. 2000;96:377-379[Free Full Text]. 6. Damle R, Wasil T, Allen S, Schulman P, Rai K, Ferrarini M, Chiorazzi N. Updated data on V gene mutation status and CD38 expression in B-CLL [letter]. Blood. 2000;95:2456-2457. 7. Hamblin T, Orchard J, Gardiner A, Oscier D, Davis Z, Stevenson F. Immunoglobulin V genes and CD38 expression in CLL [letter]. Blood. 2000;95:2455-2456. 8. Rassenti LZ, Kipps TJ. Lack of allelic exclusion in B cell chronic lymphocytic leukemia. J Exp Med. 1997;185:1435-1445[Abstract/Free Full Text]. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Articles in Blood Online: Ig V Gene Mutation Status and CD38 Expression As Novel Prognostic Indicators in Chronic Lymphocytic Leukemia Rajendra N. Damle, Tarun Wasil, Franco Fais, Fabio Ghiotto, Angelo Valetto, Steven L. Allen, Aby Buchbinder, Daniel Budman, Klaus Dittmar, Jonathan Kolitz, Stuart M. Lichtman, Philip Schulman, Vincent P. Vinciguerra, Kanti R. Rai, Manlio Ferrarini, and Nicholas Chiorazzi Blood 1999 94: 1840-1847. [Abstract] [Full Text] [PDF] Unmutated Ig VH Genes Are Associated With a More Aggressive Form of Chronic Lymphocytic Leukemia Terry J. Hamblin, Zadie Davis, Anne Gardiner, David G. Oscier, and Freda K. Stevenson Blood 1999 94: 1848-1854. [Abstract] [Full Text] [PDF] Immunoglobulin V genes and CD38 expression in CLL T. J. Hamblin, J. A. Orchard, A. Gardiner, D. G. Oscier, Z. Davis, F. K. 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Use of IGHV3-21 in chronic lymphocytic leukemia is associated with high-risk disease and reflects antigen-driven, post-germinal center leukemogenic selection Blood, May 15, 2008; 111(10): 5101 - 5108. [Abstract] [Full Text] [PDF] G. Roos, A. Krober, P. Grabowski, D. Kienle, A. Buhler, H. Dohner, R. Rosenquist, and S. Stilgenbauer Short telomeres are associated with genetic complexity, high-risk genomic aberrations, and short survival in chronic lymphocytic leukemia Blood, February 15, 2008; 111(4): 2246 - 2252. [Abstract] [Full Text] [PDF] A. W. Hauswirth and U. Jager Impact of cytogenetic and molecular prognostic markers on the clinical management of chronic lymphocytic leukemia Haematologica, January 1, 2008; 93(1): 14 - 19. [Full Text] [PDF] E. Backman, A.-C. Bergh, I. Lagerdahl, B. Rydberg, C. Sundstrom, G. Tobin, R. Rosenquist, M. Linderholm, and A. Rosen Thioredoxin, produced by stromal cells retrieved from the lymph node microenvironment, rescues chronic lymphocytic leukemia cells from apoptosis in vitro Haematologica, November 1, 2007; 92(11): 1495 - 1504. [Abstract] [Full Text] [PDF] L. V. Abruzzo, L. L. Barron, K. Anderson, R. J. Newman, W. G. Wierda, S. O'Brien, A. Ferrajoli, M. Luthra, S. Talwalkar, R. Luthra, et al. Identification and Validation of Biomarkers of IgVH Mutation Status in Chronic Lymphocytic Leukemia Using Microfluidics Quantitative Real-Time Polymerase Chain Reaction Technology J. Mol. Diagn., September 1, 2007; 9(4): 546 - 555. [Abstract] [Full Text] [PDF] K. W. L. Yee and S. M. O'Brien Chronic Lymphocytic Leukemia: Diagnosis and Treatment Mayo Clin. Proc., August 1, 2006; 81(8): 1105 - 1129. [Abstract] [Full Text] [PDF] M. Thorselius, A. Krober, F. Murray, U. Thunberg, G. Tobin, A. Buhler, D. Kienle, E. Albesiano, R. Maffei, L.-P. Dao-Ung, et al. Strikingly homologous immunoglobulin gene rearrangements and poor outcome in VH3-21-using chronic lymphocytic leukemia patients independent of geographic origin and mutational status Blood, April 1, 2006; 107(7): 2889 - 2894. [Abstract] [Full Text] [PDF] R. Marasca, R. Maffei, M. Morselli, P. Zucchini, I. Castelli, S. Martinelli, M. Fontana, S. Ravanetti, M. Curotti, G. Leonardi, et al. Immunoglobulin Mutational Status Detected through Single-Round Amplification of Partial VH Region Represents a Good Prognostic Marker for Clinical Outcome in Chronic Lymphocytic Leukemia J. Mol. Diagn., November 1, 2005; 7(5): 566 - 574. [Abstract] [Full Text] [PDF] P. Grabowski, M. Hultdin, K. Karlsson, G. Tobin, A. Aleskog, U. Thunberg, A. Laurell, C. Sundstrom, R. Rosenquist, and G. Roos Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation status Blood, June 15, 2005; 105(12): 4807 - 4812. [Abstract] [Full Text] [PDF] N. Chiorazzi, K. 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ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile Blood, June 15, 2003; 101(12): 4944 - 4951. [Abstract] [Full Text] [PDF] G. Tobin, U. Thunberg, A. Johnson, I. Eriksson, O. Soderberg, K. Karlsson, M. Merup, G. Juliusson, J. Vilpo, G. Enblad, et al. Chronic lymphocytic leukemias utilizing the VH3-21 gene display highly restricted V{lambda}2-14 gene use and homologous CDR3s: implicating recognition of a common antigen epitope Blood, June 15, 2003; 101(12): 4952 - 4957. [Abstract] [Full Text] [PDF] F. I. Camacho, P. Algara, A. Rodriguez, E. Ruiz-Ballesteros, M. Mollejo, N. Martinez, J. A. Martinez-Climent, M. Gonzalez, M. Mateo, A. Caleo, et al. Molecular heterogeneity in MCL defined by the use of specific VH genes and the frequency of somatic mutations Blood, May 15, 2003; 101(10): 4042 - 4046. [Abstract] [Full Text] [PDF] S. H. Walsh, M. Thorselius, A. Johnson, O. Soderberg, M. Jerkeman, E. Bjorck, I. Eriksson, U. Thunberg, O. Landgren, M. Ehinger, et al. Mutated VH genes and preferential VH3-21 use define new subsets of mantle cell lymphoma Blood, May 15, 2003; 101(10): 4047 - 4054. [Abstract] [Full Text] [PDF] P. Ghia, G. Guida, S. Stella, D. Gottardi, M. Geuna, G. Strola, C. Scielzo, and F. Caligaris-Cappio The pattern of CD38 expression defines a distinct subset of chronic lymphocytic leukemia (CLL) patients at risk of disease progression Blood, February 15, 2003; 101(4): 1262 - 1269. [Abstract] [Full Text] [PDF] S. Lanham, T. Hamblin, D. Oscier, R. Ibbotson, F. Stevenson, and G. Packham Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia Blood, February 1, 2003; 101(3): 1087 - 1093. [Abstract] [Full Text] [PDF] J. C. Byrd, B. L. Peterson, V. A. Morrison, K. Park, R. Jacobson, E. Hoke, J. W. Vardiman, K. Rai, C. A. Schiffer, and R. A. Larson Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712) Blood, January 1, 2003; 101(1): 6 - 14. [Abstract] [Full Text] [PDF] D. G. Oscier, A. C. Gardiner, S. J. Mould, S. Glide, Z. A. Davis, R. E. Ibbotson, M. M. Corcoran, R. M. Chapman, P. W. Thomas, J. A. Copplestone, et al. Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors Blood, July 30, 2002; 100(4): 1177 - 1184. [Abstract] [Full Text] [PDF] A. Krober, T. Seiler, A. Benner, L. Bullinger, E. Bruckle, P. Lichter, H. Dohner, and S. Stilgenbauer VH mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia Blood, July 30, 2002; 100(4): 1410 - 1416. [Abstract] [Full Text] [PDF] K. Lin, P. D. Sherrington, M. Dennis, Z. Matrai, J. C. Cawley, and A. R. Pettitt Relationship between p53 dysfunction, CD38 expression, and IgVH mutation in chronic lymphocytic leukemia Blood, July 30, 2002; 100(4): 1404 - 1409. [Abstract] [Full Text] [PDF] N. Ishibe, M. Albitar, I. B. Jilani, L. R. Goldin, G. E. Marti, and N. E. Caporaso CXCR4 expression is associated with survival in familial chronic lymphocytic leukemia, but CD38 expression is not Blood, July 18, 2002; 100(3): 1100 - 1101. [Full Text] [PDF] G. Tobin, U. Thunberg, A. Johnson, I. Thorn, O. Soderberg, M. Hultdin, J. Botling, G. Enblad, J. Sallstrom, C. Sundstrom, et al. Somatically mutated Ig VH3-21 genes characterize a new subset of chronic lymphocytic leukemia Blood, March 15, 2002; 99(6): 2262 - 2264. [Abstract] [Full Text] [PDF] T. J. Hamblin, J. A. Orchard, R. E. Ibbotson, Z. Davis, P. W. Thomas, F. K. Stevenson, and D. G. Oscier CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease Blood, February 1, 2002; 99(3): 1023 - 1029. [Abstract] [Full Text] [PDF] K. R. Rai, H. Dohner, M. J. Keating, and E. Montserrat Chronic Lymphocytic Leukemia: Case-Based Session Hematology, January 1, 2001; 2001(1): 140 - 156. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) 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 Thunberg, U. Articles by Ferrarini, M. 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