Skip to main content

Thank you for visiting 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.

Chronic Lymphocytic Leukemia

Molecular heterogeneity in chronic lymphocytic leukemia is dependent on BCR signaling: clinical correlation


Chronic lymphocytic leukemia (CLL), the most frequent form of adult leukemia in Western countries, is characterized by a highly variable clinical course. Expression profiling of a series of 160 CLL patients allowed interrogating the genes presumably playing a role in pathogenesis, relating the expression of functionally relevant signatures with the time to treatment. First, we identified genes relevant to the biology and prognosis of CLL to build a CLL disease-specific oligonucleotide microarray. Second, we hybridized a training series on the CLL-specific chip, generating a biology-based predictive model. Finally, this model was validated in a new CLL series. Clinical variability in CLL is related with the expression of two gene clusters, associated with B-cell receptor (BCR) signaling and mitogen-activated protein kinase (MAPK) activation, including nuclear factor-κB1 (NF-κB1). The expression of these clusters identifies three risk-score groups with treatment-free survival probabilities at 5 years of 83, 50 and 17%. This molecular predictor can be applied to early clinical stages of CLL. This signature is related to immunoglobulin variable region somatic hypermutation and surrogate markers. There is a molecular heterogeneity in CLL, dependent on the expression of genes defining BCR and MAPK/NF-κB clusters, which can be used to predict time to treatment in early clinical stages.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



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

Figure 1
Figure 2
Figure 3

Accession codes




  1. Dighiero G . CLL biology and prognosis. Hematology (Am Soc Hematol Educ Program) 2005; 1: 278–284.

    Article  Google Scholar 

  2. Chiorazzi N, Rai KR, Ferrarini M . Chronic lymphocytic leukemia. N Engl J Med 2005; 352: 804–815.

    Article  CAS  Google Scholar 

  3. 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  Google Scholar 

  4. Rai KR, Montserrat E . Prognostic factors in chronic lymphocytic leukemia. Semin Hematol 1987; 24: 252–256.

    CAS  PubMed  Google Scholar 

  5. 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 

  6. 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  Google Scholar 

  7. 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 

  8. 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  Google Scholar 

  9. 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  Google Scholar 

  10. Durig J, Naschar M, Schmucker U, Renzing-Kohler K, Holter T, Huttmann A et al. CD38 expression is an important prognostic marker in chronic lymphocytic leukaemia. Leukemia 2002; 16: 30–35.

    Article  CAS  Google Scholar 

  11. 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  Google Scholar 

  12. 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 

  13. 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  Google Scholar 

  14. Van't Veer MB, Brooijmans AM, Langerak AW, Verhaaf B, Goudswaard CS, Graveland WJ et al. The predictive value of lipoprotein lipase for survival in chronic lymphocytic leukemia. Haematologica 2006; 91: 56–63.

    CAS  PubMed  Google Scholar 

  15. Oppezzo P, Vasconcelos Y, Settegrana C, Jeannel D, Vuillier F, Legarff-Tavernier M et al. The LPL/ADAM29 expression ratio is a novel prognosis indicator in chronic lymphocytic leukemia. Blood 2005; 106: 650–657.

    Article  CAS  Google Scholar 

  16. Heintel D, Kienle D, Shehata M, Krober A, Kroemer E, Schwarzinger I et al. High expression of lipoprotein lipase in poor risk B-cell chronic lymphocytic leukemia. Leukemia 2005; 19: 1216–1223.

    Article  CAS  Google Scholar 

  17. 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  Google Scholar 

  18. 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  Google Scholar 

  19. 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 

  20. Tracey L, Villuendas R, Ortiz P, Dopazo A, Spiteri I, Lombardia L et al. Identification of genes involved in resistance to interferon-alpha in cutaneous T-cell lymphoma. Am J Pathol 2002; 161: 1825–1837.

    Article  CAS  Google Scholar 

  21. Rodriguez A, Martinez N, Camacho FI, Ruiz-Ballesteros E, Algara P, Garcia JF et al. Variability in the degree of expression of phosphorylated IkappaBalpha in chronic lymphocytic leukemia cases with nodal involvement. Clin Cancer Res 2004; 10: 6796–6806.

    Article  CAS  Google Scholar 

  22. Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 2004; 351: 2159–2169.

    Article  CAS  Google Scholar 

  23. Stevenson FK, Caligaris-Cappio F . Chronic lymphocytic leukemia: revelations from the B-cell receptor. Blood 2004; 103: 4389–4395.

    Article  CAS  Google Scholar 

  24. Ingham RJ, Santos L, Dang-Lawson M, Holgado-Madruga M, Dudek P, Maroun CR et al. The Gab1 docking protein links the b cell antigen receptor to the phosphatidylinositol 3-kinase/Akt signaling pathway and to the SHP2 tyrosine phosphatase. J Biol Chem 2001; 276: 12257–12265.

    Article  CAS  Google Scholar 

  25. Raman C, Kuo A, Deshane J, Litchfield DW, Kimberly RP . Regulation of casein kinase 2 by direct interaction with cell surface receptor CD5. J Biol Chem 1998; 273: 19183–19189.

    Article  CAS  Google Scholar 

  26. Su TT, Guo B, Kawakami Y, Sommer K, Chae K, Humphries LA et al. PKC-beta controls I kappa B kinase lipid raft recruitment and activation in response to BCR signaling. Nat Immunol 2002; 3: 780–786.

    Article  CAS  Google Scholar 

  27. Leitges M, Sanz L, Martin P, Duran A, Braun U, Garcia JF et al. Targeted disruption of the zetaPKC gene results in the impairment of the NF-kappaB pathway. Mol Cell 2001; 8: 771–780.

    Article  CAS  Google Scholar 

  28. Nakano H, Oshima H, Chung W, Williams-Abbott L, Ware CF, Yagita H et al. TRAF5, an activator of NF-kappaB and putative signal transducer for the lymphotoxin-beta receptor. J Biol Chem 1996; 271: 14661–14664.

    Article  CAS  Google Scholar 

  29. Nishiu M, Yanagawa R, Nakatsuka S, Yao M, Tsunoda T, Nakamura Y et al. Microarray analysis of gene-expression profiles in diffuse large B-cell lymphoma: identification of genes related to disease progression. Jpn J Cancer Res 2002; 93: 894–901.

    Article  CAS  Google Scholar 

  30. Garcia-Cao I, Lafuente MJ, Criado LM, Diaz-Meco MT, Serrano M, Moscat J . Genetic inactivation of Par4 results in hyperactivation of NF-kappaB and impairment of JNK and p38. EMBO Rep 2003; 4: 307–312.

    Article  CAS  Google Scholar 

  31. Park MY, Jang HD, Lee SY, Lee KJ, Kim E . Fas-associated factor-1 inhibits nuclear factor-kappaB (NF-kappaB) activity by interfering with nuclear translocation of the RelA (p65) subunit of NF-kappaB. J Biol Chem 2004; 279: 2544–2549.

    Article  CAS  Google Scholar 

  32. Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 2005; 353: 1793–1801.

    Article  CAS  Google Scholar 

  33. Huttmann A, Klein-Hitpass L, Thomale J, Deenen R, Carpinteiro A, Nuckel H et al. Gene expression signatures separate B-cell chronic lymphocytic leukaemia prognostic subgroups defined by ZAP-70 and CD38 expression status. Leukemia 2006; 20: 1774–1782.

    Article  CAS  Google Scholar 

  34. 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  Google Scholar 

Download references


We thank the Tumour Bank Network of the CNIO for the coordination of shipment of samples. Francisco Cifuentes is a full-time employee of the company Agilent Technologies, whose custom product ‘8-pack microarray’ platform was used in the present study.

Author information

Authors and Affiliations



Corresponding author

Correspondence to M A Piris.

Additional information

Financial support: This study was supported by grants from the Ministerio de Sanidad y Consumo (G03/179, PI051623) and the Ministerio de Ciencia y Tecnología (SAF2005-00221, SAF2004-04286), Spain. Antonia Rodríguez was supported by a grant from the Asociación Española Contra el Cáncer (AECC).

Supplementary Information accompanies the paper on the Leukemia web site (

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Rodríguez, A., Villuendas, R., Yáñez, L. et al. Molecular heterogeneity in chronic lymphocytic leukemia is dependent on BCR signaling: clinical correlation. Leukemia 21, 1984–1991 (2007).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


This article is cited by


Quick links