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Chronic Lymphocytic Leukemia and Normal B Cells

High expression of lipoprotein lipase in poor risk B-cell chronic lymphocytic leukemia

Leukemia volume 19, pages 1216–1223 (2005)Cite this article

Abstract

We investigated the pattern of lipoprotein lipase (LPL) expression in B-cell chronic lymphocytic leukemia (B-CLL) and assessed its prognostic relevance. Expression of LPL mRNA as well as protein was highly restricted to leukemic B cells. The intensity of intracellular immunoreactivity of LPL was higher in samples of patients with unmutated immunoglobulin heavy-chain variable region genes (IGVH) compared to those with mutated IGVH genes. LPL mRNA levels in peripheral blood mononuclear cells (PBMNC) from 104 CLL patients differed by 1.5 orders of magnitude between cases with mutated (N=51) or unmutated (N=53) IGVH (median: 1.33 vs 45.22 compared to normal PBMNC). LPL expression correlated strongly with IGVH mutational status (R=0.614; P<0.0001). High LPL expression predicted unmutated IGVH status with an odds ratio of 25.90 (P<0.0001) and discriminated between mutated and unmutated cases in 87 of 104 patients (84%). LPL expression was higher in patients with poor risk cytogenetics. High LPL expression was associated with a shorter treatment-free survival (median 40 vs 96 months, P=0.001) and a trend for a shorter median overall survival (105 months vs not reached). Our data establish LPL as a prognostic marker and suggest functional consequences of LPL overexpression in patients with B-CLL.

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References

  1. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS . Clinical staging of chronic lymphocytic leukemia. Blood 1975; 46: 219–234.

    CAS  PubMed  Google Scholar 

  2. Binet JL, Lepoprier M, Dighiero G, Charron D, D'Athis P, Vaugier G et al. A clinical staging system for chronic lymphocytic leukemia: prognostic significance. Cancer 1977; 40: 855–864.

    Article  CAS  PubMed  Google Scholar 

  3. Rozman C, Montserrat E . Chronic lymphocytic leukemia. N Engl J Med 1995; 333: 1052–1057.

    Article  CAS  PubMed  Google Scholar 

  4. Kipps TJ . Chronic lymphocytic leukemia. Curr Opin Hematol 2000; 7: 223–234.

    Article  CAS  PubMed  Google Scholar 

  5. Montserrat E, Sanchez-Bisono J, Vinolas N, Rozman C . Lymphocyte doubling time in chronic lymphocytic leukaemia: analysis of its prognostic significance. Br J Haematol 1986; 62: 567–575.

    Article  CAS  PubMed  Google Scholar 

  6. Reinisch W, Willheim M, Hilgarth M, Gasche C, Mader R, Szepfalusi S et al. Soluble CD23 reliably reflects disease activity in B-cell chronic lymphocytic leukemia. J Clin Oncol 1994; 12: 2146–2152.

    Article  CAS  PubMed  Google Scholar 

  7. Hallek M, Langenmayer I, Nerl C, Knauf W, Dietzfelbinger H, Adorf D et al. Elevated serum thymidine kinase levels identify a subgroup at high risk of disease progression in early, nonsmoldering chronic lymphocytic leukemia. Blood 1999; 93: 1732–1737.

    CAS  PubMed  Google Scholar 

  8. Heintel D, Schwarzinger I, Chizzali-Bonfadin C, Thalhammer R, Schwarzmeier J, Fritzer-Szekeres M et al. Association of CD38 antigen expression with other prognostic parameters in early stages of chronic lymphocytic leukemia. Leukemia Lymphoma 2001; 42: 1315–1321.

    Article  CAS  PubMed  Google Scholar 

  9. 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 

  10. Dohner H, Stilgenbauer S, James MR, Benner A, Weilguni T, Bentz M et al. 11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis. Blood 1997; 89: 2516–2522.

    CAS  PubMed  Google Scholar 

  11. 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 

  12. 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 

  13. 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 

  14. 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 

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

    CAS  PubMed  Google Scholar 

  16. Vasconcelos Y, Davi F, Levy V, Oppezzo P, Magnac C, Michel A et al. Binet's staging system and VH genes are independent but complementary prognostic indicators in chronic lymphocytic leukemia. J Clin Oncol 2003; 21: 3928–3932.

    Article  CAS  PubMed  Google Scholar 

  17. Thunberg U, Johnson A, Roos G, Thorn I, Tobin G, Sallstrom J et al. CD38 expression is a poor predictor for VH gene mutational status and prognosis in chronic lymphocytic leukemia. Blood 2001; 97: 1892–1894.

    Article  CAS  PubMed  Google Scholar 

  18. Stilgenbauer S, Bullinger L, Lichter P, Dohner H, German CLL Study Group (GCLLSG). Chronic lymphocytic leukemia. Genetics of chronic lymphocytic leukemia: genomic aberrations and V(H) gene mutation status in pathogenesis and clinical course. Leukemia 2002; 16: 993–1007.

    Article  CAS  PubMed  Google Scholar 

  19. Guarini A, Gaidano G, Mauro FR, Capello D, Mancini F, De Propris MS et al. Chronic lymphocytic leukemia patients with highly stable and indolent disease show distinctive phenotypic and genotypic features. Blood 2003; 102: 4497–4506.

    Article  Google Scholar 

  20. Rosenwald A, Alizadeh AA, Widhopf G, Simon R, Davis RE, Yu X et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 2001; 194: 1639–1647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Klein U, Tu Y, Stolovitzky GA, Mattioli M, Cattoretti G, Husson H 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: 1625–1638.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chen L, Widhopf G, Huynh L, Rassenti L, Rai KR, Weiss A et al. Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia. Blood 2002; 100: 4609–4614.

    Article  CAS  PubMed  Google Scholar 

  23. Wiestner A, Rosenwald A, Barry TS, Wright G, Davis RE, Henrickson SE et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood 2003; 101: 4944–4951.

    Article  CAS  PubMed  Google Scholar 

  24. Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M et al. ZAP-70 expression as a surrogate for immunoglobulin–variable–region mutations in chronic lymphocytic leukemia. N Engl J Med 2003; 348: 1764–1775.

    Article  CAS  PubMed  Google Scholar 

  25. Rai KR, Chiorazzi N . Determining the clinical course and outcome in chronic lymphocytic leukemia. N Engl J Med 2003; 348: 1797–1799.

    Article  PubMed  Google Scholar 

  26. Durig J, Nuckel H, Cremer M, Fuhrer A, Halfmeyer K, Fandrey J et al. ZAP-70 expression is a prognostic factor in chronic lymphocytic leukemia. Leukemia 2003; 17: 2426–2434.

    Article  CAS  PubMed  Google Scholar 

  27. Orchard JA, Ibbotson RE, Davis Z, Wiestner A, Rosenwald A, Thomas PW et al. ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet 2004; 363: 105–111.

    Article  CAS  PubMed  Google Scholar 

  28. Oppezzo P, Vuillier F, Vasconcelos Y, Dumas G, Magnac C, Payelle-Brogard B et al. Chronic lymphocytic leukemia B cells expressing AID display a dissociation between class switch recombination and somatic hypermutation. Blood 2003; 101: 4029–4032.

    Article  CAS  PubMed  Google Scholar 

  29. McCarthy H, Wierda WG, Barron LL, Cromwell CC, Wang J, Coombes KR et al. High expression of activation-induced cytidine deaminase (AID) and splice variants is a distinctive feature of poor prognosis chronic lymphocytic leukemia. Blood 2003; 101: 4903–4908.

    Article  CAS  PubMed  Google Scholar 

  30. Albesiano E, Messmer BT, Damle RN, Allen SL, Rai KR, Chiorazzi N . Activation-induced cytidine deaminase in chronic lymphocytic leukemia B cells: expression as multiple forms in a dynamic, variably sized fraction of the clone. Blood 2003; 102: 3333–3339.

    Article  CAS  PubMed  Google Scholar 

  31. Heintel D, Kroemer E, Kienle D, Schwarzinger I, Gleiss A, Schwarzmeier J, et al., German CLL Study Group. High expression of activation-induced cytidine deaminase (AID) mRNA is associated with unmutated IGVH gene status and unfavourable cytogenetic aberrations in patients with chronic lymphocytic leukaemia. Leukemia 2004; 18: 756–762.

    Article  CAS  PubMed  Google Scholar 

  32. Mead JR, Irvine SA, Ramji DP . Lipoprotein lipase: structure, function, regulation, and role in disease. J Mol Med 2002; 80: 753–769.

    Article  CAS  PubMed  Google Scholar 

  33. Merkel M, Kako Y, Radner H, Cho IS, Ramasamy R, Brunzell JD et al. Catalytically inactive lipoprotein lipase expression in muscle of transgenic mice increases very low density lipoprotein uptake: direct evidence that lipoprotein lipase bridging occurs in vivo. Proc Natl Acad Sci USA 1998; 95: 13841–13846.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mamputu JC, Renier G . Differentiation of human monocytes to monocyte-derived macrophages is associated with increased lipoprotein lipase-induced tumor necrosis factor-alpha expression and production: a process involving cell surface proteoglycans and protein kinase C. Arterioscler Thromb Vasc Biol 1999; 19: 1405–1411.

    Article  CAS  PubMed  Google Scholar 

  35. Peterson J, Fujimuto W, Brunzell J . Human lipoprotein lipase: relation of activity, heparin affinity, and confirmation as studied with monoclonal antibodies. J Lipid Res 1992; 33: 1165–1170.

    CAS  PubMed  Google Scholar 

  36. Armitage P, Colton T . Encyclopaedia of Biostatistics, Vol. 1. Chichester, UK: John Wiley and Sons, 1998.

    Google Scholar 

  37. Heinze G, Schemper M . A solution to the problem of separation in logistic regression. Stat Med 2002; 21: 2409–2419.

    Article  PubMed  Google Scholar 

  38. Rassenti LZ, Huynh L, Toy TL, Chen L, Keating MJ, Gribben JG et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med 2004; 351: 893–901.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We wish to thank Bernd Biermayer, Uli Zeman and Martin Hilgarth for excellent technical assistance and John D Brunzell from the University of Washington, Seattle, who kindly provided the LPL 5D2 Mab. This work was supported by grants from the Austrian National Bank (Grant #9964), the Austrian Human Genome Project (‘GEN-AU’) (UJ, DH), Corixa Co., Seattle (AG), DFG (STI 296/1), Sander (2001.04.01) and Fresenius (CLL4) (DK, AK, HD, SS).

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Authors and Affiliations

  1. Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria

    D Heintel, M Shehata, D Mitteregger, T Le, J Schwarzmeier, A Gaiger & U Jäger

  2. Department of Internal Medicine III, University of Ulm, Ulm, Germany

    D Kienle, A Kröber, H Döhner & S Stilgenbauer

  3. Department of Medical Biology, Medical University of Vienna, Vienna, Austria

    E Kroemer & C Fonatsch

  4. Department of Clinical Chemistry and Laboratory Medicine, Medical University of Vienna, Vienna, Austria

    I Schwarzinger & C Mannhalter

  5. Department of Medical Computer Sciences, Section of Clinical Biometrics, Medical University of Vienna, Vienna, Austria

    A Gleiß

  6. Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria

    A Chott

  7. Center of Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna, Austria

    D Heintel & U Jäger

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Heintel, D., Kienle, D., Shehata, M. et al. High expression of lipoprotein lipase in poor risk B-cell chronic lymphocytic leukemia. Leukemia 19, 1216–1223 (2005). https://doi.org/10.1038/sj.leu.2403748

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