Immunologic Research

, Volume 49, Issue 1–3, pp 269–280 | Cite as

Immunologic aspects of monoclonal B-cell lymphocytosis

  • Mark C. LanasaEmail author
  • J. Brice Weinberg


Monoclonal B-cell lymphocytosis (MBL) is a preclinical hematologic condition wherein small numbers of clonal B cells can be detected in the blood of otherwise healthy individuals. Most MBL have a surface immunophenotype nearly identical to that of chronic lymphocytic leukemia (CLL), though other phenotypes can also be identified. MBL has been shown to be a precursor state for CLL, but most MBL clones are quite small and apparently have minimal potential to progress of CLL or other B-cell lymphoproliferative disorder (B-LPD). The investigation of MBL as a precursor state for CLL will likely lead to important insights into mechanisms of disease pathogenesis. The review will cover clinical and translational aspects of MBL, with a particular emphasis on the prevalence of MBL; the relationship between MBL, CLL, and other B-LPDs; and the capacity of MBL to modulate the normal B- and T-cell compartments.


Monoclonal B lymphocytosis Chronic lymphocytic leukemia Non-Hodgkin’s lymphoma B-cell receptor B-cell development 



MC Lanasa is a fellow of the Leukemia and Lymphoma Society of America. This research was supported by the Leukemia and Lymphoma Society of America, the Bernstein Fund for Leukemia Research, the VA Research Service, and a grant from the National Institutes of Health (NCI R03 CA128030). Flow Cytometry was performed in the Duke Human Vaccine Institute Flow Cytometry Core Facility that is supported by the National Institutes of Health award AI-51445. The Genetic Epidemiology of CLL (GEC) Consortium is supported by NIH grants CA118444 and CA92153; the Intramural Research Program of the NIH, National Cancer Institute; and CLL Research Consortium. Additional support was provided by 1 UL1 RR024150 from the National Center for Research Resources (NCRR), a component of NIH and the NIH Roadmap for Medical Research, the Veterans Affairs Research Service, and CA15083 from the National Cancer Institute. The GEC member institutions are The Mayo Clinic (lead site; PI: Susan Slager, Ph.D.), Duke University, The M.D. Anderson Cancer Center, The National Cancer Institute, The University of California at San Diego, The University of Minnesota, and The University of Utah.


  1. 1.
    Altekruse SF, Kosary CL, Krapcho M, Neyman N, Aminou R, Waldron W, Ruhl J, Howlader N, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Cronin K, Chen HS, Feuer EJ, Stinchcomb DG, Edwards BK (eds). SEER cancer statistics review, 1975–2007. 2010. Bethesda, MD: National Cancer Institute., based on November 2009 SEER data submission, posted to the SEER web site.
  2. 2.
    Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352(8):804–15.PubMedCrossRefGoogle Scholar
  3. 3.
    Rawstron AC, et al. Monoclonal B lymphocytes with the characteristics of “indolent” chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts. Blood. 2002;100(2):635–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Rawstron AC, et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med. 2008;359(6):575–83.PubMedCrossRefGoogle Scholar
  5. 5.
    Landgren O, et al. B-cell clones as early markers for chronic lymphocytic leukemia. N Engl J Med. 2009;360(7):659–67.PubMedCrossRefGoogle Scholar
  6. 6.
    Rawstron AC, et al. Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion. Blood. 2002;100(7):2289–90.PubMedCrossRefGoogle Scholar
  7. 7.
    Ghia P, et al. Monoclonal CD5 + and CD5 − B-lymphocyte expansions are frequent in the peripheral blood of the elderly. Blood. 2004;103(6):2337–42.PubMedCrossRefGoogle Scholar
  8. 8.
    Shim YK, et al. Prevalence and natural history of monoclonal and polyclonal B-cell lymphocytosis in a residential adult population. Cytometry B Clin Cytom. 2007;72(5):344–53.PubMedGoogle Scholar
  9. 9.
    Nieto WG, et al. Increased frequency (12%) of circulating chronic lymphocytic leukemia-like B-cell clones in healthy subjects using a highly sensitive multicolor flow cytometry approach. Blood. 2009;114(1):33–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Nieto WG, et al. Commentary: Comparison of current flow cytometry methods for monoclonal B cell lymphocytosis detection. Cytometry B Clin Cytom. 2010;78 Suppl 1:S4–9.Google Scholar
  11. 11.
    Shim YK, et al. Prevalence of monoclonal B-cell lymphocytosis: a systematic review. Cytometry B Clin Cytom. 2010;78 Suppl 1:S10–8.Google Scholar
  12. 12.
    Lanasa MC, et al. Single-cell analysis reveals oligoclonality among ‘low-count’ monoclonal B-cell lymphocytosis. Leukemia. 2010;24(1):133–40.PubMedCrossRefGoogle Scholar
  13. 13.
    Marti GE, et al. B-cell monoclonal lymphocytosis and B-cell abnormalities in the setting of familial B-cell chronic lymphocytic leukemia. Cytometry B Clin Cytom. 2003;52(1):1–12.PubMedCrossRefGoogle Scholar
  14. 14.
    Goldin LR et al. Common occurrence of monoclonal B-cell lymphocytosis among members of high-risk CLL families. Br J Haematol. 2010 (in press).Google Scholar
  15. 15.
    Matos DM, Ismael SJ, Scrideli CA, de Oliveira FM, Rego EM, Falcao RP. Monoclonal B-cell lymphocytosis in first-degree relatives of patients with sporadic (non-familial) chronic lymphocytic leukaemia. Br J Haematol. 2009;147:339–46.PubMedCrossRefGoogle Scholar
  16. 16.
    Crowther-Swanepoel D et al. Inherited genetic susceptibility to monoclonal B-cell lymphocytosis. Blood. 2010 (in press).Google Scholar
  17. 17.
    Goldin LR, et al. Elevated risk of chronic lymphocytic leukemia and other indolent non-Hodgkin’s lymphomas among relatives of patients with chronic lymphocytic leukemia. Haematologica. 2009;94(5):647–53.PubMedCrossRefGoogle Scholar
  18. 18.
    Shanafelt TD et al. Monoclonal B-cell lymphocytosis (MBL): biology, natural history and clinical management. Leukemia. 2010;24(3):512–20.Google Scholar
  19. 19.
    Marti GE, et al. Diagnostic criteria for monoclonal B-cell lymphocytosis. Br J Haematol. 2005;130(3):325–32.PubMedCrossRefGoogle Scholar
  20. 20.
    Cheson BD, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996;87(12):4990–7.PubMedGoogle Scholar
  21. 21.
    Hallek M, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the international workshop on chronic lymphocytic leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446–56.PubMedCrossRefGoogle Scholar
  22. 22.
    Shanafelt TD, et al. B-cell count and survival: differentiating chronic lymphocytic leukemia from monoclonal B-cell lymphocytosis based on clinical outcome. Blood. 2009;113(18):4188–96.PubMedCrossRefGoogle Scholar
  23. 23.
    Shanafelt TD, et al. Brief report: natural history of individuals with clinically recognized monoclonal B-cell lymphocytosis compared with patients with Rai 0 chronic lymphocytic leukemia. J Clin Oncol. 2009;27(24):3959–63.PubMedCrossRefGoogle Scholar
  24. 24.
    Rawstron AC, et al. Different biology and clinical outcome according to the absolute numbers of clonal B-cells in monoclonal B-cell lymphocytosis (MBL). Cytometry B Clin Cytom. 2010;78 Suppl 1:S19–23.Google Scholar
  25. 25.
    Hauswirth A et al. Monoclonal B-cell lymphocytosis (MBL) with normal whole lymphocyte counts is associated with reduced numbers of normal circulating immature and mature B-lymphocytes. Hematologica. 95(Suppl 2):324 (abstract).Google Scholar
  26. 26.
    Dagklis A, et al. The immunoglobulin gene repertoire of low-count chronic lymphocytic leukemia (CLL)-like monoclonal B lymphocytosis is different from CLL: diagnostic implications for clinical monitoring. Blood. 2009;114(1):26–32.PubMedCrossRefGoogle Scholar
  27. 27.
    Caligaris-Cappio F, Ghia P. Novel insights in chronic lymphocytic leukemia: are we getting closer to understanding the pathogenesis of the disease? J Clin Oncol. 2008;26(27):4497–503.PubMedCrossRefGoogle Scholar
  28. 28.
    Fais F, et al. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J Clin Invest. 1998;102(8):1515–25.PubMedCrossRefGoogle Scholar
  29. 29.
    Widhopf GF II, et al. Chronic lymphocytic leukemia B cells of more than 1% of patients express virtually identical immunoglobulins. Blood. 2004;104(8):2499–504.PubMedCrossRefGoogle Scholar
  30. 30.
    Tobin G, et al. Subsets with restricted immunoglobulin gene rearrangement features indicate a role for antigen selection in the development of chronic lymphocytic leukemia. Blood. 2004;104(9):2879–85.PubMedCrossRefGoogle Scholar
  31. 31.
    Messmer BT, et al. Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia. J Exp Med. 2004;200(4):519–25.PubMedCrossRefGoogle Scholar
  32. 32.
    Hamblin TJ, et al. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94(6):1848–54.PubMedGoogle Scholar
  33. 33.
    Rosenwald A, et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med. 2001;194(11):1639–47.PubMedCrossRefGoogle Scholar
  34. 34.
    Klein U, et al. Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med. 2001;194(11):1625–38.PubMedCrossRefGoogle Scholar
  35. 35.
    Guarini A, et al. BCR ligation induced by IgM stimulation results in gene expression and functional changes only in IgV H unmutated chronic lymphocytic leukemia (CLL) cells. Blood. 2008;112(3):782–92.PubMedCrossRefGoogle Scholar
  36. 36.
    Volkheimer AD, et al. Progressive immunoglobulin gene mutations in chronic lymphocytic leukemia: evidence for antigen-driven intraclonal diversification. Blood. 2007;109(4):1559–67.PubMedCrossRefGoogle Scholar
  37. 37.
    Lossos IS, et al. The inference of antigen selection on Ig genes. J Immunol. 2000;165(9):5122–6.PubMedGoogle Scholar
  38. 38.
    Bagnara D, et al. IgV gene intraclonal diversification and clonal evolution in B-cell chronic lymphocytic leukaemia. Br J Haematol. 2006;133(1):50–8.PubMedGoogle Scholar
  39. 39.
    Gurrieri C, 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(5):629–39.PubMedCrossRefGoogle Scholar
  40. 40.
    Markey GM, et al. Enumeration of absolute numbers of T lymphocyte subsets in B-chronic lymphocytic leukaemia using an immunoperoxidase technique: relation to clinical stage. Br J Haematol. 1986;62(2):257–73.PubMedCrossRefGoogle Scholar
  41. 41.
    Kimby E, et al. T lymphocyte subpopulations in chronic lymphocytic leukemia of B cell type in relation to immunoglobulin isotype(s) on the leukemic clone and to clinical features. Eur J Haematol. 1987;38(3):261–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Ghia P, Caligaris-Cappio F. The indispensable role of microenvironment in the natural history of low-grade B-cell neoplasms. Adv Cancer Res. 2000;79:157–73.PubMedCrossRefGoogle Scholar
  43. 43.
    Gorgun G, et al. Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells. J Clin Invest. 2005;115(7):1797–805.PubMedCrossRefGoogle Scholar
  44. 44.
    Ramsay AG, et al. Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J Clin Invest. 2008;118(7):2427–37.PubMedGoogle Scholar
  45. 45.
    Lotz M, Ranheim E, Kipps TJ. Transforming growth factor beta as endogenous growth inhibitor of chronic lymphocytic leukemia B cells. J Exp Med. 1994;179(3):999–1004.PubMedCrossRefGoogle Scholar
  46. 46.
    Fayad L, et al. Interleukin-6 and interleukin-10 levels in chronic lymphocytic leukemia: correlation with phenotypic characteristics and outcome. Blood. 2001;97(1):256–63.PubMedCrossRefGoogle Scholar
  47. 47.
    Beyer M, et al. Reduced frequencies and suppressive function of CD4 + CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood. 2005;106(6):2018–25.PubMedCrossRefGoogle Scholar
  48. 48.
    Motta M, et al. Increased expression of CD152 (CTLA-4) by normal T lymphocytes in untreated patients with B-cell chronic lymphocytic leukemia. Leukemia. 2005;19(10):1788–93.PubMedCrossRefGoogle Scholar
  49. 49.
    Rezvany MR, et al. Oligoclonal TCRBV gene usage in B-cell chronic lymphocytic leukemia: major perturbations are preferentially seen within the CD4 T-cell subset. Blood. 1999;94(3):1063–9.PubMedGoogle Scholar
  50. 50.
    Goolsby CL, et al. Expansions of clonal and oligoclonal T cells in B-cell chronic lymphocytic leukemia are primarily restricted to the CD3(+)CD8(+) T-cell population. Cytometry. 2000;42(3):188–95.PubMedCrossRefGoogle Scholar
  51. 51.
    Serrano D, et al. Clonal expansion within the CD4 + CD57 + and CD8 + CD57 + T cell subsets in chronic lymphocytic leukemia. J Immunol. 1997;158(3):1482–9.PubMedGoogle Scholar
  52. 52.
    Miller C, et al. Facultative role of germinal centers and T cells in the somatic diversification of IgVH genes. J Exp Med. 1995;181(4):1319–31.PubMedCrossRefGoogle Scholar
  53. 53.
    Fischer M, Klein U, Kuppers R. Molecular single-cell analysis reveals that CD5-positive peripheral blood B cells in healthy humans are characterized by rearranged Vkappa genes lacking somatic mutation. J Clin Invest. 1997;100(7):1667–76.PubMedCrossRefGoogle Scholar
  54. 54.
    Palmer S, et al. Prognostic importance of T and NK-cells in a consecutive series of newly diagnosed patients with chronic lymphocytic leukaemia. Br J Haematol. 2008;141(5):607–14.PubMedCrossRefGoogle Scholar
  55. 55.
    Lanasa MC, et al. Oligoclonal TRBV gene usage among CD8(+) T cells in monoclonal B lymphocytosis and CLL. Br J Haematol. 2009;145(4):535–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Kepler TB, et al. Statistical analysis of antigen receptor spectratype data. Bioinformatics. 2005;21(16):3394–400.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of MedicineDuke University Medical CenterDurhamUSA
  2. 2.Department of MedicineDuke University Medical CenterDurhamUSA
  3. 3.Department of ImmunologyDuke University Medical CenterDurhamUSA
  4. 4.Durham Veterans Affairs Medical CenterDurhamUSA

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