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Myeloma

Clinical significance of CD81 expression by clonal plasma cells in high-risk smoldering and symptomatic multiple myeloma patients

Leukemia volume 26, pages 1862–1869 (2012)Cite this article

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Abstract

The presence of CD19 in myelomatous plasma cells (MM-PCs) correlates with adverse prognosis in multiple myeloma (MM). Although CD19 expression is upregulated by CD81, this marker has been poorly investigated and its prognostic value in MM remains unknown. We have analyzed CD81 expression by multiparameter flow cytometry in MM-PCs from 230 MM patients at diagnosis included in the Grupo Español de Mieloma (GEM)05>65years trial as well as 56 high-risk smoldering MM (SMM). CD81 expression was detected in 45% (103/230) MM patients, and the detection of CD81+ MM-PC was an independent prognostic factor for progression-free (hazard ratio=1.9; P=0.003) and overall survival (hazard ratio=2.0; P=0.02); this adverse impact was validated in an additional series of 325 transplant-candidate MM patients included in the GEM05 <65 years trial. Moreover, CD81+ SMM (n=34/56, 57%) patients had a shorter time to progression to MM (P=0.02). Overall, our results show that CD81 may have a relevant role in MM pathogenesis and represent a novel adverse prognostic marker in myeloma.

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References

  1. Gutierrez NC, Castellanos MV, Martin ML, Mateos MV, Hernandez JM, Fernandez M et al. Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis. Leukemia 2007; 21: 143–150.

    Article  CAS  Google Scholar 

  2. Gutierrez NC, Garcia JL, Hernandez JM, Lumbreras E, Castellanos M, Rasillo A et al. Prognostic and biologic significance of chromosomal imbalances assessed by comparative genomic hybridization in multiple myeloma. Blood 2004; 104: 2661–2666.

    Article  CAS  Google Scholar 

  3. Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood 2007; 109: 3489–3495.

    Article  CAS  Google Scholar 

  4. Shaughnessy Jr JD, Zhan F, Burington BE, Huang Y, Colla S, Hanamura I et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 2007; 109: 2276–2284.

    Article  CAS  Google Scholar 

  5. Mateo G, Montalban MA, Vidriales MB, Lahuerta JJ, Mateos MV, Gutierrez N et al. Prognostic value of immunophenotyping in multiple myeloma: a study by the PETHEMA/GEM cooperative study groups on patients uniformly treated with high-dose therapy. J Clin Oncol 2008; 26: 2737–2744.

    Article  Google Scholar 

  6. Bahlis NJ, King AM, Kolonias D, Carlson LM, Liu HY, Hussein MA et al. CD28-mediated regulation of multiple myeloma cell proliferation and survival. Blood 2007; 109: 5002–5010.

    Article  CAS  Google Scholar 

  7. Bataille R, Jego G, Robillard N, Barille-Nion S, Harousseau JL, Moreau P et al. The phenotype of normal, reactive and malignant plasma cells. Identification of “many and multiple myelomas” and of new targets for myeloma therapy. Haematologica 2006; 91: 1234–1240.

    CAS  Google Scholar 

  8. Tedder TF, Inaoki M, Sato S . The CD19-CD21 complex regulates signal transduction thresholds governing humoral immunity and autoimmunity. Immunity 1997; 6: 107–118.

    Article  CAS  Google Scholar 

  9. Cherukuri A, Carter RH, Brooks S, Bornmann W, Finn R, Dowd CS et al. B cell signaling is regulated by induced palmitoylation of CD81. J Biol Chem 2004; 279: 31973–31982.

    Article  CAS  Google Scholar 

  10. Cherukuri A, Shoham T, Sohn HW, Levy S, Brooks S, Carter R et al. The tetraspanin CD81 is necessary for partitioning of coligated CD19/CD21-B cell antigen receptor complexes into signaling-active lipid rafts. J Immunol 2004; 172: 370–380.

    Article  CAS  Google Scholar 

  11. Shoham T, Rajapaksa R, Boucheix C, Rubinstein E, Poe JC, Tedder TF et al. The tetraspanin CD81 regulates the expression of CD19 during B cell development in a postendoplasmic reticulum compartment. J Immunol 2003; 171: 4062–4072.

    Article  CAS  Google Scholar 

  12. van Zelm MC, Smet J, Adams B, Mascart F, Schandene L, Janssen F et al. CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency. J Clin Invest 2010; 120: 1265–1274.

    Article  CAS  Google Scholar 

  13. Barrena S, Almeida J, Yunta M, Lopez A, Fernandez-Mosteirin N, Giralt M et al. Aberrant expression of tetraspanin molecules in B-cell chronic lymphoproliferative disorders and its correlation with normal B-cell maturation. Leukemia 2005; 19: 1376–1383.

    Article  CAS  Google Scholar 

  14. Luo RF, Zhao S, Tibshirani R, Myklebust JH, Sanyal M, Fernandez R et al. CD81 protein is expressed at high levels in normal germinal center B cells and in subtypes of human lymphomas. Hum Pathol 2009; 41: 271–280.

    Article  Google Scholar 

  15. Carloni V, Mazzocca A, Ravichandran KS . Tetraspanin CD81 is linked to ERK/MAPKinase signaling by Shc in liver tumor cells. Oncogene 2004; 23: 1566–1574.

    Article  CAS  Google Scholar 

  16. Mateos MV, Oriol A, Martinez-Lopez J, Gutierrez N, Teruel AI, de Paz R et al. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol 2010; 11: 934–941.

    Article  CAS  Google Scholar 

  17. Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. BrJHaematol 1998; 102: 1115–1123.

    CAS  Google Scholar 

  18. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003; 121: 749–757.

    Article  Google Scholar 

  19. Paiva B, Martinez-Lopez J, Vidriales M, Mateos M, Montalban M, Fernandez-Redondo E et al. Comparison of immunofixation, serum free light chain, and immunophenotyping for response evaluation and prognostication in multiple myeloma. J Clin Oncol 2011; 29: 1627–1633.

    Article  CAS  Google Scholar 

  20. Mateo Manzanera G, San Miguel Izquierdo J, Orfao de Matos A . Immunophenotyping of plasma cells in multiple myeloma. Methods Mol Med 2005; 113: 5–24.

    Google Scholar 

  21. Fonseca R, Bergsagel PL, Drach J, Shaughnessy J, Gutierrez N, Stewart K et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia 2009; 23: 2210–2221.

    Article  CAS  Google Scholar 

  22. Gutierrez NC, Sarasquete ME, Misiewicz-Krzeminska I, Delgado M, De Las Rivas J, Ticona FV et al. Deregulation of microRNA expression in the different genetic subtypes of multiple myeloma and correlation with gene expression profiling. Leukemia 2010; 24: 629–637.

    Article  CAS  Google Scholar 

  23. Esparís-Ogando A, Alegre A, Aguado B, Mateo G, Gutiérrez N, Bladé J et al. Bortezomib is an efficient agent in plasma cell leukemias. Int J Cancer 2005; 114: 665–667.

    Article  Google Scholar 

  24. Greipp PR, San MJ, Durie BG, Crowley JJ, Barlogie B, Blade J et al. International Staging System for multiple myeloma. J Clin Oncol 2005; 23: 3412–3420.

    Article  Google Scholar 

  25. Avet-Loiseau H, Li C, Magrangeas F, Gouraud W, Charbonnel C, Harousseau J et al. Prognostic significance of copy-number alterations in multiple myeloma. J Clin Oncol 2009; 27: 4585–4590.

    Article  CAS  Google Scholar 

  26. Fonseca R, Blood E, Rue M, Harrington D, Oken MM, Kyle RA et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 2003; 101: 4569–4575.

    Article  CAS  Google Scholar 

  27. Zhan F, Huang Y, Colla S, Stewart J, Hanamura I, Gupta S et al. The molecular classification of multiple myeloma. Blood 2006; 108: 2020–2028.

    Article  CAS  Google Scholar 

  28. Broyl A, Hose D, Lokhorst H, de Knegt Y, Peeters J, Jauch A et al. Gene expression profiling for molecular classification of multiple myeloma in newly diagnosed patients. Blood 2010; 116: 2543–2553.

    Article  CAS  Google Scholar 

  29. Walker B, Wardell C, Chiecchio L, Smith E, Boyd K, Neri A et al. Aberrant global methylation patterns affect the molecular pathogenesis and prognosis of multiple myeloma. Blood 2011; 117: 553–562.

    Article  CAS  Google Scholar 

  30. Mateo G, Castellanos M, Rasillo A, Gutierrez NC, Montalban MA, Martin ML et al. Genetic abnormalities and patterns of antigenic expression in multiple myeloma. Clin Cancer Res 2005; 11: 3661–3667.

    Article  CAS  Google Scholar 

  31. 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 

  32. Schroers R, Griesinger F, Trümper L, Haase D, Kulle B, Klein-Hitpass L et al. Combined analysis of ZAP-70 and CD38 expression as a predictor of disease progression in B-cell chronic lymphocytic leukemia. Leukemia 2005; 19: 750–758.

    Article  CAS  Google Scholar 

  33. Kyle RA, Rajkumar SV . Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009; 23: 3–9.

    Article  CAS  Google Scholar 

  34. Maecker H, Levy S . Normal lymphocyte development but delayed humoral immune response in CD81-null mice. J Exp Med 1997; 185: 1505–1510.

    Article  CAS  Google Scholar 

  35. Miyazaki T, Müller U, Campbell K . Normal development but differentially altered proliferative responses of lymphocytes in mice lacking CD81. EMBO J 1997; 16: 4217–4225.

    Article  CAS  Google Scholar 

  36. Tsitsikov E, Gutierrez-Ramos J, Geha R . Impaired CD19 expression and signaling, enhanced antibody response to type II T independent antigen and reduction of B-1 cells in CD81-deficient mice. Proc Natl Acad Sci USA 1997; 94: 10844–10849.

    Article  CAS  Google Scholar 

  37. Shoham T, Rajapaksa R, Kuo C, Haimovich J, Levy S . Building of the tetraspanin web: distinct structural domains of CD81 function in different cellular compartments. Mol Cell Biol 2006; 26: 1373–1385.

    Article  CAS  Google Scholar 

  38. Perez-Persona E, Vidriales MB, Mateo G, Garcia-Sanz R, Mateos MV, de Coca AG et al. New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells. Blood 2007; 110: 2586–2592.

    Article  CAS  Google Scholar 

  39. Kyle R, Remstein E, Therneau T, Dispenzieri A, Kurtin P, Hodnefield J et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 2007; 356: 2582–2590.

    Article  CAS  Google Scholar 

  40. Korde N, Kristinsson S, Landgren O . Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies. Blood 2011; 117: 5573–5581.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Cooperative Research Thematic Network (RTICs; RD06/0020/0006, RD06/0020/0005, RD06/0020/0031, RD06/0020/0101, RD06/0020/1056, RD06/0020/0041 and G03/136), MM Jevitt, SL firm, the Instituto de Salud Carlos III/ Subdirección General de Investigación Sanitaria (FIS: PI060339; 06/1354; 02/0905; 01/0089/01-02; PS09/01897/01370) and Consejería de Sanidad, Junta de Castilla y León, Valladolid, Spain (557/A/10).

Author contributions

JFSM, BP and AO conceived the idea, and together with MBV designed the study protocol; BP, MBV, MAB and JJP analyzed the flow cytometry data; NCG analyzed the GEP data; XC and ED performed research and analyzed the myeloma cell lines data; LR, AO, JML, MVM, LLC, EFR, JGL, FA, LP, MAE, MJT, RP, AM, JH, YG, RM, JB and JJL contributed with provision of study material or patients; BP, MBV, NCG, XC, ED, AP and JFSM analyzed and interpreted data; BP and ED performed statistical analysis; and BP and JFSM wrote the manuscript. All authors reviewed and approved the manuscript.

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Authors and Affiliations

  1. Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Salamanca, Spain

    B Paiva, N-C Gutiérrez, M-B Vídriales, M-V Mateos, L López-Corral, J-J Pérez & J-F San Miguel

  2. Servicio de Hematología, Centro de Investigación del Cáncer (CIC, IBMCC USAL-CSIC), Salamanca, Spain

    B Paiva, N-C Gutiérrez, X Chen, M-B Vídriales, M-V Mateos, L López-Corral, E Díaz-Rodríguez, J-J Pérez, A Orfao, A Pandiella & J-F San Miguel

  3. Servicio de Hematología, Hospital 12 de Octubre, Madrid, Spain

    M-Á Montalbán, J Martínez-López, E Fernández-Redondo & J-J Lahuerta

  4. Servicio de Hematología, Hospital Clínic, IDIBAPS, Barcelona, Spain

    L Rosiñol & J Bladé

  5. Servicio de Hematología, Hospital Universitari Germans Trias i Pujol, Badalona, Spain

    A Oriol

  6. Servicio de Hematología, Hospital Morales Meseguer, Murcia, Spain

    F de Arriba

  7. Servicio de Hematología, Hospital Lozano Blesa, Zaragoza, Spain

    L Palomera

  8. Servicio de Hematología, Hospital de Donostia, San Sebastian, Spain

    E Bengoechea

  9. Servicio de Hematología, Hospital Clínico de Valencia, Valencia, Spain

    M-J Terol

  10. Servicio de Hematología, Hospital Universitario La Paz, Madrid, Spain

    R de Paz

  11. Servicio de Hematología, Hospital Virgen de la Concha, Zamora, Spain

    A Martin

  12. Servicio de Hematología, Hospital General de Segovia, Segovia, Spain

    J Hernández

  13. Servicio General de Citometría and Department of Medicine, Universidad de Salamanca, Salamanca, Spain

    A Orfao

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on behalf of the GEM (Grupo Español de Mieloma)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) cooperative study groups

Corresponding author

Correspondence to J-F San Miguel.

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Competing interests

BP, AO, LR, FdA, LP and J-JL have received honoraria from Celgene and Janssen-Cilag. M-VM has served on the speaker's bureau for Millennium, Celgene and Janssen-Cilag. JB has received honoraria and has served on the advisory board for Janssen-Cilag and Celgene, as well as grant support from Celgene and Janssen-Cilag. J-FSM has served on the speaker's bureau and on the advisory board for, and has received honoraria from, Millennium, Jansen-Cilag and Celgene. All other authors declare no conflict of interest.

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Paiva, B., Gutiérrez, NC., Chen, X. et al. Clinical significance of CD81 expression by clonal plasma cells in high-risk smoldering and symptomatic multiple myeloma patients. Leukemia 26, 1862–1869 (2012). https://doi.org/10.1038/leu.2012.42

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