Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

Chronic Lymphocytic Leukemia, Normal T and B cells (CLL)

CD38 expression levels in chronic lymphocytic leukemia B cells are associated with activation marker expression and differential responses to interferon stimulation

Abstract

CD38, a surface protein whose expression increases upon normal B-cell activation, is a marker of disease aggression in B-cell chronic lymphocytic leukemia (B-CLL). Higher percentages of CD38-expressing CLL B cells may be found in lymphoid compartments compared to peripheral blood. Therefore, it is possible that although CLL B cells are resting, CD38 may be a marker of recent cell activation prior to entry into the periphery. To address this hypothesis, we examined the association of CD38 expression with other activation antigens identified in gene expression profiling experiments and include CD18, CD49d, CD20, and subunit 5 of the anaphase-promoting complex/cyclosome. We found that all these markers were more highly expressed in leukemic B cells from CD38-positive CLL patients. Lastly, because interferon is known to modulate CD38 expression, we used IFN-α to test the ability of CLL B cells to increase CD38 expression in vitro. Interestingly, IFN stimulation only modulated CD38 expression in CLL B cells that already expressed CD38. Taken together, these data suggest that CD38 is a marker of a more recently activated CLL B cell. This in turn may explain the biological and clinical differences between CD38-positive type B-CLL and CD38-negative type B-CLL.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 5
Figure 1
Figure 2
Figure 3
Figure 4
Figure 6

Similar content being viewed by others

References

  1. 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 

  2. Hamblin TJ, Orchard JA, Gardiner A, Oscier DG . Immunoglobulin V genes and CD38 expression in CLL. Blood 2000; 95: 2455–2457.

    CAS  PubMed  Google Scholar 

  3. 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  Google Scholar 

  4. Jelinek DF, Tschumper RC, Geyer SM, Bone ND, Dewald GW, Hanson CA et al. Analysis of clonal B-cell CD38 and immunoglobulin variable region sequence status in relation to clinical outcome for B-chronic lymphocytic leukemia. Br J Haematol 2001; 115: 854–861.

    Article  CAS  Google Scholar 

  5. D’Arena G, Musto P, Cascavilla N, Dell’Olio M, Di Renzo N, Perla G et al. CD38 expression correlates with adverse biological features and predicts poor clinical outcome in B-cell chronic lymphocytic leukemia. Leukemia Lymphoma 2001; 42: 109–114.

    Article  Google Scholar 

  6. Del Poeta G, Maurillo L, Venditti A, Buccisano F, Epiceno AM, Capelli G et al. Clinical significance of CD38 expression in chronic lymphocytic leukemia. Blood 2001; 98: 2633–2639.

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  8. Ghia P, Guida G, Stella S, Gottardi D, Geuna M, Strola G et al. The pattern of CD38 expression defines a distinct subset of chronic lymphocytic leukemia (CLL) patients at risk of disease progression. Blood 2003; 101: 1262–1269.

    Article  CAS  Google Scholar 

  9. Ibrahim S, Keating M, Do KA, O’Brien S, Huh YO, Jilani I et al. CD38 expression as an important prognostic factor in B-cell chronic lymphocytic leukemia. Blood 2001; 98: 181–186.

    Article  CAS  Google Scholar 

  10. 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  Google Scholar 

  11. Chang C-C, Cleveland RP . Conversion of CD38 and/or myeloid-associated marker expression status during the course of B-CLL: association with a change to an aggressive clinical course. Blood 2002; 100: 1106.

    Article  CAS  Google Scholar 

  12. Deaglio S, Capobianco A, Bergui L, Durig J, Morabito F, Duhrsen U et al. CD38 is a signaling molecule in B-cell chronic lymphocytic leukemia cells. Blood 2003; 102: 2146–2155.

    Article  CAS  Google Scholar 

  13. Deaglio S, Mehta K, Malavasi F . Human CD38: a (r)evolutionary story of enzymes and receptors. Leukemia Res 2001; 25: 1–12.

    Article  CAS  Google Scholar 

  14. Zupo S, Rugari E, Dono M, Taborelli G, Malavasi F, Ferrarini M . CD38 signaling by agonistic monoclonal antibody prevents apoptosis of human germinal center B cells. Eur J Immunol 1994; 24: 1218–1222.

    Article  CAS  Google Scholar 

  15. Dianzani U, Funaro A, DiFranco D, Garbarino G, Bragardo M, Redoglia V et al. Interaction between endothelium and CD4+CD45RA+ lymphocytes. Role of the human CD38 molecule. J Immunol 1994; 153: 952–954.

    CAS  PubMed  Google Scholar 

  16. Wheeler K, Gordon J . Co-ligation of surface IgM and CD40 on naïve B lymphocytes generates a blast population with an ambiguous extrafollicular/germinal centre cell phenotype. Int Immunol 1996; 8: 815–828.

    Article  CAS  Google Scholar 

  17. Dang LH, Rock KL . Stimulation of B lymphocytes through surface Ig receptors induces LFA-1 and ICAM-1-dependent adhesion. J Immunol 1991; 146: 3273–3279.

    CAS  PubMed  Google Scholar 

  18. Postigo AA, Sanchz-Mateos P, Lazarovits AI, Sanchez-Madrid F, de Landazuri MO . α4β7 integrin mediates B cell binding to fibronectin and vascular cell adhesion molecule-1. J Immunol 1993; 151: 2471–2483.

    CAS  PubMed  Google Scholar 

  19. Deaglio S, Vaisitti T, Bergui L, Bonello L, Horenstein AL, Tamagnone L et al. CD38 and CD100 lead a network of surface receptors relaying positive signals for B-CLL growth and survival. Blood 2005; 105: 3042–3050.

    Article  CAS  Google Scholar 

  20. Galibert B, Burdin N, de Saint-Vis B, Garrone P, Van Kooten C, Banchereau J et al. CD40 and B cell antigen receptor dual triggering of resting B lymphocytes turns on a partial germinal center phenotype. J Exp Med 1996; 183: 77–85.

    Article  CAS  Google Scholar 

  21. Musso T, Deaglio S, Franco L, Calosso L, Badolato R, Garbarino G et al. CD38 expression and functional activities are up-regulated by IFN-γ on human monocytes and monocytic cell lines. J Leukocyte Biol 2001; 69: 605–612.

    CAS  PubMed  Google Scholar 

  22. Bauvois B, Durant L, Laboureau J, Barthelemy E, Rouillard D, Boulla G et al. Upregulation of CD38 gene expression in leukemic B cells by interferon types I and II. J Interferon Cytokine Res 1999; 19: 1059–1066.

    Article  CAS  Google Scholar 

  23. Stacchini A, Aragno M, Vallario A, Alfarano A, Circosta P, Gottardi D et al. MEC1 and MEC2: two new cell lines derived from B-chronic lymphocytic leukaemia in prolymphocytoid transformation. Leukemia Res 1999; 23: 127–136.

    Article  CAS  Google Scholar 

  24. Pribila JT, Quale AC, Mueller KL, Shimuzu Y . Integrins and T cell-mediated immunity. Annu Rev Immunol 2004; 22: 157–180.

    Article  CAS  Google Scholar 

  25. Anolik J, Looney RJ, Bottaro A, Sanz I, Young F . Down-regulation of CD20 on B cells upon CD40 activation. Eur J Immunol 2003; 33: 2398–2409.

    Article  CAS  Google Scholar 

  26. Arpin C, Dechanet J, Van Kooten C, Merville P, Grouard G, Briere F et al. Generation of memory B cells and plasma cells in vitro. Science 1995; 268: 720–722.

    Article  CAS  Google Scholar 

  27. Zachariae W, Nasmyth K . Whose end is destruction: cell division and the anaphase-promoting complex. Genes Dev 1999; 13: 2039–2058.

    Article  CAS  Google Scholar 

  28. Bohnhorst JO, Bjorgan MB, Thoen JE, Natvig JB, Thompson KM . Bm1–Bm5 classification of peripheral blood B cells reveals circulating germinal center founder cells in healthy individuals and disturbance in the B cell subpopulations in patients with primary Sjogren's syndrome. J Immunol 2001; 167: 3610–3618.

    Article  CAS  Google Scholar 

  29. Arce E, Jackson DG, Gill MA, Bennett LB, Banchereau J, Pascual V . Increased frequency of pre-germinal center B cells and plasma cell precursors in the blood of children with systemic lupus erythematosus. J Immunol 2001; 167: 2361–2369.

    Article  CAS  Google Scholar 

  30. Durig J, Nuckel H, Huttmann A, Kruse E, Holter T, Halfmeyer K et al. Expression of ribosomal and translation-associated genes is correlated with a favorable clinical course in chronic lymphocytic leukemia. Blood 2003; 101: 2748–2755.

    Article  CAS  Google Scholar 

  31. Bentley AM, Williams BC, Goldberg ML, Andres AJ . Phenotypic characterization of Drosophila ida mutants: defining the role of APC5 in cell cycle progression. J Cell Sci 2002; 115: 949–951.

    CAS  PubMed  Google Scholar 

  32. Manocha S, Matrai Z, Osthoff M, Carter A, Pettitt AR . Correlaton between cell size and CD38 expression in chronic lymphocytic leukaemia. Leukemia Lymphoma 2003; 44: 797–800.

    Article  CAS  Google Scholar 

  33. Zupo S, Isnardi L, Megna M, Massara R, Malavasi F, Dono M et al. CD38 expression distinguishes two groups of B-cell chronic lymphocytic leukemias with different responses to anti-IgM antibodies and propensity to apoptosis. Blood 1996; 88: 1365–1374.

    CAS  PubMed  Google Scholar 

  34. Lanham S, Hamblin T, Oscier D, Ibbotson R, Stevenson F, Packham G . Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia. Blood 2003; 101: 1087–1093.

    Article  CAS  Google Scholar 

  35. Ferrero E, Malavasi F . Human CD38, a leukocyte receptor and ectoenzyme, is a member of a novel eukaryotic gene family of nicotinamide adenine dinucleotide-converting enzymes. J Immunol 1997; 159: 3858–3865.

    CAS  PubMed  Google Scholar 

  36. Zupo S, Massara R, Dono M, Rossi E, Malavasi F, Cosulich ME et al. Apoptosis or plasma cell differentiation of B-chronic lymphocytic leukemia cells induced by cross-linking of surface IgM or IgD. Blood 2000; 95: 1199–1206.

    CAS  PubMed  Google Scholar 

  37. Rush LJ, Plass C . Alterations of DNA methylation in hematologic malignancies. Cancer Lett 2002; 185: 1–12.

    Article  CAS  Google Scholar 

  38. Fulop Z, Csernus B, Timar B, Szepesi A, Matolcsy A . Microsatellite instability and hMLH1 promotor hypermethylation in Richter's transformation of chronic lymphocytic leukemia. Leukemia 2003; 17: 411–415.

    Article  CAS  Google Scholar 

  39. Jaksic O, Paro MMK, Skelin IK, Kusec R, Pejsa V, Jaksic B . CD38 on B-cell chronic lymphocytic leukemia cells has higher expression in lymph nodes than in peripheral blood or bone marrow. Blood 2004; 103: 1968–1969.

    Article  CAS  Google Scholar 

  40. Messmer BT, Messmer D, Allen SL, Kolitz JE, Kudalkar P, Cesaar D et al. In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. J Clin Invest 2005; 115: 755–764.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Bonnie Arendt, Nancy Bone, Cheryl Jankiewicz, and Renee Tschumper for their technical assistance, Dr Karla Ballman and Bruce Morlan for their assistance in analyzing the exploratory gene expression study data, and Dr Clive Zent for his insightful comments. This study was supported by the National Institutes of Health Training Grant T32-HL67742 (BTP), R01 CA91942 (NEK), and generous philanthropic support provided by Mr Edson Spencer.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to D F Jelinek.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pittner, B., Shanafelt, T., Kay, N. et al. CD38 expression levels in chronic lymphocytic leukemia B cells are associated with activation marker expression and differential responses to interferon stimulation. Leukemia 19, 2264–2272 (2005). https://doi.org/10.1038/sj.leu.2403975

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403975

Keywords

This article is cited by

Search

Quick links