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Bcl-6 mutation status provides clinically valuable information in early-stage B-cell chronic lymphocytic leukemia

Leukemia volume 18, pages 743–746 (2004)Cite this article

Abstract

In B-cell chronic lymphocytic leukemia (B-CLL), somatic mutation of IgVH genes defines a subgroup with favorable prognosis, whereas the absence of IgVH mutations is correlated with a worse outcome. Mutations of the BCL-6 gene are also observed in a subset of B-CLL, but the clinical significance of this molecular alteration remains uncertain. We examined the distribution of IgVH and BCL-6 gene mutations in 95 well-characterized patients with Binet stage A B-CLL, and correlated them with clinical, laboratory, cytogenetic findings and disease progression. Mutations of the BCL-6 gene were observed only in cases harboring mutated IgVH. Unexpectedly, coexistence of IgVH and BCL-6 mutations was correlated with shorter treatment-free interval (TFI) compared to cases harboring only IgVH mutation (median, 55 months vs not reached; P=0.01), resembling the clinical course of unmutated IgVH cases (median TFI, 44 months). As expected, deletions of 17p13 (P53 locus) and 11q22 (ATM locus) were observed in cases with unmutated IgVH, except one patient who showed mutations of both IgVH and BCL-6. No other statistically significant differences were observed among the genetic subgroups. Our data indicate that BCL-6 mutations identify a subgroup of Binet stage A B-CLL patients with a high risk of progression despite the presence of mutated IgVH gene.

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References

  1. Rozman C, Monserrat E . Chronic lymphocytic leukemia. N Engl J Med 1995; 1333: 1052–1057.

    Article  Google Scholar 

  2. Schroeder HJ, Dighiero G . The pathogenesis of chronic lymphocytic leukemia: analysis of the antibody repertoire. Immunol Today 1994; 15: 288–294.

    Article  CAS  PubMed  Google Scholar 

  3. Fais F, Ghiotto F, Hashimoto S, Sellars B, Valetto A, Allen SL et al. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J Clin Invest 1998; 102: 1515–1525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94: 1840–1847.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  6. Dyer MJS, Oscier DG . The configuration of the immunoglobulin genes in B cell chronic lymphocytic leukemia. Leukemia 2002; 16: 973–984.

    Article  CAS  PubMed  Google Scholar 

  7. Oscier DG, Gardiner AC, Mould SJ, Glide S, Davis ZA, Ibbotson RE 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 2002; 100: 1177–1184.

    CAS  PubMed  Google Scholar 

  8. Lin K, Sherrington PD, Dennis M, Matrai Z, Cawley JC, Pettitt AR . Relationship between P53 dysfunction, CD38 expression, and IGVH mutation in chronic lymphocytic leukemia. Blood 2002; 100: 1404–1409.

    Article  CAS  PubMed  Google Scholar 

  9. Kröber A, Seiler T, Benner A, Bullinger L, Bruckle E, Lichter P et al. VH mutation status, CD38 expression, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 2002; 100: 1410–1416.

    PubMed  Google Scholar 

  10. Pasqualucci L, Migliazza A, Fracchiolla N, William C, Neri A, Baldini L et al. BCL-6 mutations in normal germinal center B cells: evidence of somatic hypermutation acting outside Ig loci. Proc Natl Acad Sci USA 1998; 95: 11816–11821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pasqualucci L, Neri A, Baldini L, Dalla-Favera R, Migliazza A . BCL-6 mutations are associated with immunoglobulin variable heavy chain mutations in B-cell chronic lymphocytic leukemia. Cancer Res 2000; 60: 5644–5648.

    CAS  PubMed  Google Scholar 

  12. Capello D, Fais F, Vivenza D, Migliaretti G, Chiorazzi N, Gaidano G et al. Identification of three subgroups of B cell chronic lymphocytic leukemia based upon mutations of BCL-6 and IgV genes. Leukemia 2000; 14: 811–815.

    Article  CAS  PubMed  Google Scholar 

  13. Sahota SS, Davis Z, Hamblin TJ, Stevenson FK . Somatic mutation of BCL-6 genes can occur in the absence of V(H) mutations in chronic lymphocytic leukemia. Blood 2000; 95: 3534–3540.

    CAS  PubMed  Google Scholar 

  14. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O’Brien S et al. National Cancer Institute-Sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87: 4990–4997.

    CAS  PubMed  Google Scholar 

  15. Miller SA, Dykes DD, Polesky HF . A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 1215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kuppers R, Zhao M, Hansmann ML, Rajewsky K . Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. EMBO J 1993; 12: 4955–4967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Migliazza A, Martinotti S, Chen W, Fusco C, Ye BH, Knowles DM et al. Frequent somatic hypermutation of the 5′ noncoding region of the BCL-6 gene in B-cell lymphoma. Proc Natl Acad Sci USA 1995; 92: 12520–12524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lossos IS, Tibshirani R, Narasimhan B, Levy R . The inference of antigen selection on Ig genes. J Immunol 2000; 165: 5122–5126.

    Article  CAS  PubMed  Google Scholar 

  19. Sanchez-Izquierdo D, Siebert R, Harder L, Marugan I, Gozzetti A, Price HP et al. Detection of translocations affecting the BCL6 locus in B cell non-Hodgkin's lymphoma by interphase fluorescence in situ hybridization. Leukemia 2001; 15: 1475–1484.

    Article  CAS  PubMed  Google Scholar 

  20. Matrai Z, Lin K, Dennis M, Sherrington P, Zuzel M, Pettitt AR et al. CD38 expression and Ig VH gene mutation in B-cell chronic lymphocytic leukemia. Blood 2001; 97: 1902–1903.

    Article  CAS  PubMed  Google Scholar 

  21. Hamblin TJ, Orchard JA, Ibbotson RE, Davis Z, Thomas PW, Stevenson FK et al. 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 2002; 99: 1023–1029.

    Article  CAS  PubMed  Google Scholar 

  22. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343: 1910–1916.

    Article  CAS  PubMed  Google Scholar 

  23. Kikuchi M, Miki T, Kumagai T, Fukuda T, Kamiyama R, Miyasaka M et al. Identification of negative regulatory regions within the first exon and intron of the BCL-6 gene. Oncogene 2000; 19: 4941–4945.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from Spanish Ministry of Health and Generalitat Valenciana. We thank the hematologists and pathologists from different institutions throughout the Valencia area for providing B-CLL samples and clinical data, and to Drs Izodore Lossos, Reiner Siebert and Martin J Dyer for critically reviewing the paper.

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Authors and Affiliations

  1. Department of Hematology and Medical Oncology, Hospital Clinico, University of Valencia, Valencia, Spain

    E Sarsotti, I Marugan, I Benet, M J Terol, D Sanchez-Izquierdo, M Tormo, F Rubio-Moscardo, J A Martinez-Climent & J García-Conde

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  1. E Sarsotti
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Correspondence to J A Martinez-Climent.

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Sarsotti, E., Marugan, I., Benet, I. et al. Bcl-6 mutation status provides clinically valuable information in early-stage B-cell chronic lymphocytic leukemia. Leukemia 18, 743–746 (2004). https://doi.org/10.1038/sj.leu.2403304

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