Immunoglobulin gene repertoire in chronic lymphocytic leukemia: Insight into antigen selection and microenvironmental interactions

Mediterranean Journal of Hematology and Infectious Diseases

Volumn 4, Issue 1, 2012, Pages

  Kostareli, Efterpi ^a,c,e,f   Gounari, Maria ^a,b,c,d   Agathangelidis, Andreas ^a,b,c,d   Stamatopoul, Kostas ^a,b  

^a G PAPANICOLAOU HOSPITAL   (Greece)

^b INFORMATION TECHNOLOGIES INSTITUTE   (Greece)

^c ARISTOTLE UNIVERSITY OF THESSALONIKI   (Greece)

^d VITA SALUTE SAN RAFFAELE UNIVERSITY   (Italy)

^e GERMAN CANCER RESEARCH CENTER   (Germany)

^f UNIVERSITY HOSPITAL HEIDELBERG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

B LYMPHOCYTE RECEPTOR; IMMUNOGLOBULIN;

ANTIGEN FUNCTION; ANTIGEN SELECTION; B LYMPHOCYTE RECEPTOR GENE; CANCER PROGNOSIS; CARCINOGENESIS; CELL INTERACTION; CHRONIC LYMPHATIC LEUKEMIA; GENE REARRANGEMENT; GENETIC ASSOCIATION; HUMAN; IMMUNOGENETICS; IMMUNOGLOBULIN GENE; IMMUNOGLOBULIN HEAVY CHAIN GENE; INTRACELLULAR SIGNALING; MOLECULAR PATHOLOGY; MUTATIONAL ANALYSIS; NONHUMAN; REVIEW; TUMOR MICROENVIRONMENT; TUMOR VOLUME;

EID: 84875973264     PISSN: None     EISSN: 20353006     Source Type: Journal    
DOI: 10.4084/MJHID.2012.052     Document Type: Review

References (84)

1. Chiorazzi, N., Rai, K. R. and Ferrarini, M., Chronic lymphocytic leukemia. N Engl J Med 2005. 352: 804-815. http://dx.doi.org/10.1056/NEJMra041720 PMid:15728813
2. Chiorazzi, N. and Ferrarini, M., Cellular origin(s) of chronic lymphocytic leukemia: cautionary notes and additional considerations and possibilities. Blood 2011. 117: 1781-1791. http://dx.doi.org/10.1182/blood-2010-07-155663 PMid:21148333 PMCid:3056635
3. Dohner, H., Stilgenbauer, S., Benner, A., Leupolt, E., Krober, A., Bullinger, L., Dohner, K., Bentz, M. and Lichter, P., Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000. 343: 1910-1916. http://dx.doi.org/10.1056/NEJM200012283432602 PMid:11136261
4. Stevenson, F. K., Krysov, S., Davies, A. J., Steele, A. J. and Packham, G., B-cell receptor signaling in chronic lymphocytic leukemia. Blood 2011. 118: 4313-4320. http://dx.doi.org/10.1182/blood-2011-06-338855 PMid:21816833
5. Cooper, M. D. and Alder, M. N., The evolution of adaptive immune systems. Cell 2006. 124: 815-822. http://dx.doi.org/10.1016/j.cell.2006.02.001 PMid:16497590
6. Janeway, C. A., Jr., Travers, P., Walport, M. and Shlomchik, M. J., Immunobiology. The immune system in health and disease. Garland Science Publishing: New York, NY 2005 2005. 6th ed..
7. Schlissel, M. S., Regulating antigen-receptor gene assembly. Nat 0 3: 890-899. http://dx.doi.org/10.1038/nri1225 Rev Immunol 2003. PMid:14668805
8. Maizels, N., Immunoglobulin gene diversification. Annu Rev Genet 2005. 39: 23-46. http://dx.doi.org/10.1146/annurev.genet.39.073003.110544 PMid:16285851
9. Fritz, E. L. and Papavasiliou, F. N., Cytidine deaminases: AIDing DNA demethylation? Genes Dev 2010. 24: 2107-2114. http://dx.doi.org/10.1101/gad.1963010
10. Liu, M. and Schatz, D. G., Balancing AID and DNA repair during somatic hypermutation. Trends Immunol 2009. 30: 173-181. http://dx.doi.org/10.1016/j.it.2009.01.007 PMid:19303358
11. Durandy, A., Taubenheim, N., Peron, S. and Fischer, A., Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies. Adv Immunol 2007. 94: 275-306. http://dx.doi.org/10.1016/S0065-2776(06)94009-7
12. Stevenson, F. K., Sahota, S. S., Ottensmeier, C. H., Zhu, D., Forconi, F. and Hamblin, T. J., The occurrence and significance of V gene mutations in B cell-derived human malignancy. Adv Cancer Res 2001. 83: 81-116. http://dx.doi.org/10.1016/S0065-230X(01)83004-9
13. Dunn-Walters, D., Thiede, C., Alpen, B. and Spencer, J., Somatic hypermutation and B-cell lymphoma. Philos Trans R Soc Lond B Biol Sci 2001. 356: 73-82. http://dx.doi.org/10.1098/rstb.2000.0751 PMid:11205334
14. Schroeder, H. W., Jr. and Dighiero, G., The pathogenesis of chronic lymphocytic leukemia: analysis of the antibody repertoire. Immunol Today 0994. 15: 288-294. http://dx.doi.org/10.1016/0167-5699(94)90009-4
15. Efremov, D. G., Ivanovski, M., Siljanovski, N., Pozzato, G., Cevreska, L., Fais, F., Chiorazzi, N., Batista, F. D. and Burrone, O. R., Restricted immunoglobulin VH region repertoire in chronic lymphocytic leukemia patients with autoimmune hemolytic anemia. Blood 0996. 87: 3869-3876. PMid:8611714
16. Hashimoto, S., Dono, M., Wakai, M., Allen, S. L., Lichtman, S. M., Schulman, P., Vinciguerra, V. P., Ferrarini, M., Silver, J. and Chiorazzi, N., Somatic diversification and selection of immunoglobulin heavy and light chain variable region genes in IgG+ CD5+ chronic lymphocytic leukemia B cells. J Exp Med 0995. 181: 1507-1517. http://dx.doi.org/10.1084/jem.181.4.1507 PMid:7535340
17. Johnson, T. A., Rassenti, L. Z. and Kipps, T. J., Ig VH1 genes expressed in B cell chronic lymphocytic leukemia exhibit distinctive molecular features. J Immunol 0997. 158: 235-246. PMid:8977195
18. Fais, F., Ghiotto, F., Hashimoto, S., Sellars, B., Valetto, A., Allen, S. L., Schulman, P., Vinciguerra, V. P., Rai, K., Rassenti, L. Z., Kipps, T. J., Dighiero, G., Schroeder, H. W., Jr., Ferrarini, M. and Chiorazzi, N., Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J Clin Invest 0998. 102: 1515-1525. http://dx.doi.org/10.1172/JCI3009 PMid:9788964 PMCid:509001
19. Damle, R. N., Wasil, T., Fais, F., Ghiotto, F., Valetto, A., Allen, S. L., Buchbinder, A., Budman, D., Dittmar, K., Kolitz, J., Lichtman, S. M., Schulman, P., Vinciguerra, V. P., Rai, K. R., Ferrarini, M. and Chiorazzi, N., Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 0999. 94: 1840-1847. PMid:10477712
20. Hamblin, T. J., Davis, Z., Gardiner, A., Oscier, D. G. and Stevenson, F. K., Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 0999. 94: 1848-1854. PMid:10477713
21. Tobin, G., Thunberg, U., Johnson, A., Thorn, I., Soderberg, O., Hultdin, M., Botling, J., Enblad, G., Sallstrom, J., Sundstrom, C., Roos, G. and Rosenquist, R., Somatically mutated Ig V(H)3-21 genes characterize a new subset of chronic lymphocytic leukemia. Blood 2002. 99: 2262-2264. http://dx.doi.org/10.1182/blood.V99.6.2262 PMid:11877310
22. Forconi, F., Sahota, S. S., Lauria, F. and Stevenson, F. K., Revisiting the definition of somatic mutational status in B-cell tumors: does 98% homology mean that a V(H)-gene is unmutated? Leukemia 2004. 18: 882-883. http://dx.doi.org/10.1038/sj.leu.2403312 PMid:14973503
23. Ghia, P., Stamatopoulos, K., Belessi, C., Moreno, C., Stilgenbauer, S., Stevenson, F., Davi, F. and Rosenquist, R., ERIC recommendations on IGHV gene mutational status analysis in chronic lymphocytic leukemia. Leukemia 2007. 21: 1-3. http://dx.doi.org/10.1038/sj.leu.2404457 PMid:17167526
24. Barbas, S. M., Ditzel, H. J., Salonen, E. M., Yang, W. P., Silverman, G. J. and Burton, D. R., Human autoantibody recognition of DNA. Proc Natl Acad Sci U S A 0995. 92: 2529-2533. http://dx.doi.org/10.1073/pnas.92.7.2529
25. Hamblin, T. J., Davis, Z. A. and Oscier, D. G., Determination of how many immunoglobulin variable region heavy chain mutations are allowable in unmutated chronic lymphocytic leukaemia - long-term follow up of patients with different percentages of mutations. Br J Haematol 2008. 140: 320-323. http://dx.doi.org/10.1111/j.1365-2141.2007.06928.x PMid:18053068
26. Murray, F., Darzentas, N., Hadzidimitriou, A., Tobin, G., Boudjogra, M., Scielzo, C., Laoutaris, N., Karlsson, K., Baran-Marzsak, F., Tsaftaris, A., Moreno, C., Anagnostopoulos, A., Caligaris-Cappio, F., Vaur, D., Ouzounis, C., Belessi, C., Ghia, P., Davi, F., Rosenquist, R. and Stamatopoulos, K., Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis. Blood 2008. 111: 1524-1533. http://dx.doi.org/10.1182/blood-2007-07-099564 PMid:17959859
27. Tobin, G., Thunberg, U., Johnson, A., Eriksson, I., Soderberg, O., Karlsson, K., Merup, M., Juliusson, G., Vilpo, J., Enblad, G., Sundstrom, C., Roos, G. and Rosenquist, R., Chronic lymphocytic leukemias utilizing the VH3-21 gene display highly restricted Vlambda2-14 gene use and homologous CDR3s: implicating recognition of a common antigen epitope. Blood 2003. 101: 4952-4957. http://dx.doi.org/10.1182/blood-2002-11-3485 PMid:12586612
28. Messmer, B. T., Albesiano, E., Efremov, D. G., Ghiotto, F., Allen, S. L., Kolitz, J., Foa, R., Damle, R. N., Fais, F., Messmer, D., Rai, K. R., Ferrarini, M. and Chiorazzi, N., Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia. J Exp Med 2004. 200: 519-525. http://dx.doi.org/10.1084/jem.20040544 PMid:15314077 PMCid:2211936
29. Widhopf, G. F., 2nd, Rassenti, L. Z., Toy, T. L., Gribben, J. G., Wierda, W. G. and Kipps, T. J., Chronic lymphocytic leukemia B cells of more than 1% of patients express virtually identical immunoglobulins. Blood 2004. 104: 2499-2504. http://dx.doi.org/10.1182/blood-2004-03-0818 PMid:15217828
30. Tobin, G., Thunberg, U., Karlsson, K., Murray, F., Laurell, A., Willander, K., Enblad, G., Merup, M., Vilpo, J., Juliusson, G., Sundstrom, C., Soderberg, O., Roos, G. and Rosenquist, R., Subsets with restricted immunoglobulin gene rearrangement features indicate a role for antigen selection in the development of chronic lymphocytic leukemia. Blood 2004. 104: 2879-2885. http://dx.doi.org/10.1182/blood-2004-01-0132 PMid:15217826
31. Zemlin, M., Klinger, M., Link, J., Zemlin, C., Bauer, K., Engler, J. A., Schroeder, H. W., Jr. and Kirkham, P. M., Expressed murine and human CDR-H3 intervals of equal length exhibit distinct repertoires that differ in their amino acid composition and predicted range of structures. J Mol Biol 2003. 334: 733-749. http://dx.doi.org/10.1016/j.jmb.2003.10.007 PMid:14636599
32. Henikoff, S. and Henikoff, J. G., Performance evaluation of amino acid substitution matrices. Proteins 0993. 17: 49-61. http://dx.doi.org/10.1002/prot.340170108 PMid:8234244
33. Stamatopoulos, K., Belessi, C., Moreno, C., Boudjograh, M., Guida, G., Smilevska, T., Belhoul, L., Stella, S., Stavroyianni, N., Crespo, M., Hadzidimitriou, A., Sutton, L., Bosch, F., Laoutaris, N., Anagnostopoulos, A., Montserrat, E., Fassas, A., Dighiero, G., Caligaris-Cappio, F., Merle-Beral, H., Ghia, P. and Davi, F., Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: Pathogenetic implications and clinical correlations. Blood 2007. 109: 259-270. http://dx.doi.org/10.1182/blood-2006-03-012948 PMid:16985177
34. Kirkham, P. M., Mortari, F., Newton, J. A. and Schroeder, H. W., Jr., Immunoglobulin VH clan and family identity predicts variable domain structure and may influence antigen binding. EMBO J 0992. 11: 603-609. PMid:1537339 PMCid:556492
35. Vargas-Madrazo, E., Lara-Ochoa, F., Ramirez-Benites, M. C. and Almagro, J. C., Evolution of the structural repertoire of the human V(H) and Vkappa germline genes. Int Immunol 0997. 9: 1801-1815. http://dx.doi.org/10.1093/intimm/9.12.1801 PMid:9466308
36. Bomben, R., Dal Bo, M., Capello, D., Forconi, F., Maffei, R., Laurenti, L., Rossi, D., Del Principe, M. I., Zucchetto, A., Bertoni, F., Rossi, F. M., Bulian, P., Cattarossi, I., Ilariucci, F., Sozzi, E., Spina, V., Zucca, E., Degan, M., Lauria, F., Del Poeta, G., Efremov, D. G., Marasca, R., Gaidano, G. and Gattei, V., Molecular and clinical features of chronic lymphocytic leukaemia with stereotyped B cell receptors: results from an Italian multicentre study. Br J Haematol 2009. 144: 492-506. http://dx.doi.org/10.1111/j.1365-2141.2008.07469.x PMid:19036101
37. Arvaniti, E., Ntoufa, S., Papakonstantinou, N., Touloumenidou, T., Laoutaris, N., Anagnostopoulos, A., Lamnissou, K., Caligaris-Cappio, F., Stamatopoulos, K., Ghia, P., Muzio, M. and Belessi, C., Toll-like receptor signaling pathway in chronic lymphocytic leukemia: distinct gene expression profiles of potential pathogenic significance in specific subsets of patients. Haematologica 2011. 96: 1644-1652. http://dx.doi.org/10.3324/haematol.2011.044792 PMid:21750087 PMCid:3208682
38. Ntoufa, S., Vardi, A., Papakonstantinou, N., Anagnostopoulos, A., Aleporou-Marinou, V., Belessi, C., Ghia, P., Caligaris-Cappio, F., Muzio, M. and Stamatopoulos, K., Distinct Innate Immunity Pathways to Activation and Tolerance in Subgroups of Chronic Lymphocytic Leukemia with Distinct Immunoglobulin Receptors. Mol Med 2012.
39. Widhopf, G. F., 2nd, Goldberg, C. J., Toy, T. L., Rassenti, L. Z., Wierda, W. G., Byrd, J. C., Keating, M. J., Gribben, J. G., Rai, K. R. and Kipps, T. J., Nonstochastic pairing of immunoglobulin heavy and light chains expressed by chronic lymphocytic leukemia B cells is predicated on the heavy chain CDR3. Blood 2008. 111: 3137-3144. http://dx.doi.org/10.1182/blood-2007-02-073130 PMid:17675554 PMCid:2265453
40. Hadzidimitriou, A., Darzentas, N., Murray, F., Smilevska, T., Arvaniti, E., Tresoldi, C., Tsaftaris, A., Laoutaris, N., Anagnostopoulos, A., Davi, F., Ghia, P., Rosenquist, R., Stamatopoulos, K. and Belessi, C., Evidence for the significant role of immunoglobulin light chains in antigen recognition and selection in chronic lymphocytic leukemia. Blood 2009. 113: 403-411. http://dx.doi.org/10.1182/blood-2008-07-166868 PMid:18948572
41. Herve, M., Xu, K., Ng, Y. S., Wardemann, H., Albesiano, E., Messmer, B. T., Chiorazzi, N. and Meffre, E., Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity. J Clin Invest 2005. 115: 1636-1643. http://dx.doi.org/10.1172/JCI24387 PMid:15902303 PMCid:1088018
42. Lanemo Myhrinder, A., Hellqvist, E., Sidorova, E., Soderberg, A., Baxendale, H., Dahle, C., Willander, K., Tobin, G., Backman, E., Soderberg, O., Rosenquist, R., Horkko, S. and Rosen, A., A new perspective: molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies. Blood 2008. 111: 3838-3848. http://dx.doi.org/10.1182/blood-2007-11-125450 PMid:18223168
43. Catera, R., Silverman, G. J., Hatzi, K., Seiler, T., Didier, S., Zhang, L., Herve, M., Meffre, E., Oscier, D. G., Vlassara, H., Scofield, R. H., Chen, Y., Allen, S. L., Kolitz, J., Rai, K. R., Chu, C. C. and Chiorazzi, N., Chronic lymphocytic leukemia cells recognize conserved epitopes associated with apoptosis and oxidation. Mol Med 2008. 14: 665-674. http://dx.doi.org/10.2119/2008-0102.Catera PMid:19009014 PMCid:2582860
44. Chu, C. C., Catera, R., Zhang, L., Didier, S., Agagnina, B. M., Damle, R. N., Kaufman, M. S., Kolitz, J. E., Allen, S. L., Rai, K. R. and Chiorazzi, N., Many chronic lymphocytic leukemia antibodies recognize apoptotic cells with exposed nonmuscle myosin heavy chain IIA: implications for patient outcome and cell of origin. Blood 2010. 115: 3907-3915. http://dx.doi.org/10.1182/blood-2009-09-244251 PMid:20110421 PMCid:2869555
45. Chu, C. C., Catera, R., Hatzi, K., Yan, X. J., Zhang, L., Wang, X. B., Fales, H. M., Allen, S. L., Kolitz, J. E., Rai, K. R. and Chiorazzi, N., Chronic lymphocytic leukemia antibodies with a common stereotypic rearrangement recognize nonmuscle myosin heavy chain IIA. Blood 2008. 112: 5122-5129. http://dx.doi.org/10.1182/blood-2008-06-162024 PMid:18812466 PMCid:2597608
46. Darzentas, N., Hadzidimitriou, A., Murray, F., Hatzi, K., Josefsson, P., Laoutaris, N., Moreno, C., Anagnostopoulos, A., Jurlander, J., Tsaftaris, A., Chiorazzi, N., Belessi, C., Ghia, P., Rosenquist, R., Davi, F. and Stamatopoulos, K., A different ontogenesis for chronic lymphocytic leukemia cases carrying stereotyped antigen receptors: molecular and computational evidence. Leukemia 2010. 24: 125-132. http://dx.doi.org/10.1038/leu.2009.186 PMid:19759557
47. Agathangelidis, A., Darzentas, N., Hadzidimitriou, A., Brochet, X., Murray, F., Yan, X. J., Davis, Z., van Gastel-Mol, E. J., Tresoldi, C., Chu, C. C., Cahill, N., Giudicelli, V., Tichy, B., Pedersen, L. B., Foroni, L., Bonello, L., Janus, A., Smedby, K., Anagnostopoulos, A., Merle-Beral, H., Laoutaris, N., Juliusson, G., di Celle, P. F., Pospisilova, S., Jurlander, J., Geisler, C., Tsaftaris, A., Lefranc, M. P., Langerak, A. W., Oscier, D. G., Chiorazzi, N., Belessi, C., Davi, F., Rosenquist, R., Ghia, P. and Stamatopoulos, K., Stereotyped B-cell receptors in one third of chronic lymphocytic leukemia: towards a molecular classification with implications for targeted therapeutic interventions. Blood 2012. http://dx.doi.org/10.1182/blood-2011-11-393694 PMid:22415752
48. Zibellini, S., Capello, D., Forconi, F., Marcatili, P., Rossi, D., Rattotti, S., Franceschetti, S., Sozzi, E., Cencini, E., Marasca, R., Baldini, L., Tucci, A., Bertoni, F., Passamonti, F., Orlandi, E., Varettoni, M., Merli, M., Rizzi, S., Gattei, V., Tramontano, A., Paulli, M., Gaidano, G. and Arcaini, L., Stereotyped patterns of B-cell receptor in splenic marginal zone lymphoma. Haematologica 2010. 95: 1792-1796. http://dx.doi.org/10.3324/haematol.2010.025437 PMid:20511668 PMCid:2948108
49. Bikos, V., Darzentas, N., Hadzidimitriou, A., Davis, Z., Hockley, S., Traverse-Glehen, A., Algara, P., Santoro, A., Gonzalez, D., Mollejo, M., Dagklis, A., Gangemi, F., Bosler, D. S., Bourikas, G., Anagnostopoulos, A., Tsaftaris, A., Iannitto, E., Ponzoni, M., Felman, P., Berger, F., Belessi, C., Ghia, P., Papadaki, T., Dogan, A., Degano, M., Matutes, E., Piris, M. A., Oscier, D. and Stamatopoulos, K., Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications. Leukemia 2012. http://dx.doi.org/10.1038/leu.2012.3 PMid:22222599
50. Hadzidimitriou, A., Agathangelidis, A., Darzentas, N., Murray, F., Delfau-Larue, M. H., Pedersen, L. B., Lopez, A. N., Dagklis, A., Rombout, P., Beldjord, K., Kolstad, A., Dreyling, M. H., Anagnostopoulos, A., Tsaftaris, A., Mavragani-Tsipidou, P., Rosenwald, A., Ponzoni, M., Groenen, P., Ghia, P., Sander, B., Papadaki, T., Campo, E., Geisler, C., Rosenquist, R., Davi, F., Pott, C. and Stamatopoulos, K., Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases. Blood 2011. 118: 3088-3095. http://dx.doi.org/10.1182/blood-2011-03-343434 PMid:21791422
51. Bomben, R., Dal-Bo, M., Benedetti, D., Capello, D., Forconi, F., Marconi, D., Bertoni, F., Maffei, R., Laurenti, L., Rossi, D., Del Principe, M. I., Luciano, F., Sozzi, E., Cattarossi, I., Zucchetto, A., Rossi, F. M., Bulian, P., Zucca, E., Nicoloso, M. S., Degan, M., Marasca, R., Efremov, D. G., Del Poeta, G., Gaidano, G. and Gattei, V., Expression of mutated IGHV3-23 genes in chronic lymphocytic leukemia identifies a disease subset with peculiar clinical and biological features. Clin Cancer Res 2010. 16: 620-628. http://dx.doi.org/10.1158/1078-0432.CCR-09-1638 PMid:20068100
52. Del Giudice, I., Chiaretti, S., Tavolaro, S., De Propris, M. S., Maggio, R., Mancini, F., Peragine, N., Santangelo, S., Marinelli, M., Mauro, F. R., Guarini, A. and Foa, R., Spontaneous regression of chronic lymphocytic leukemia: clinical and biologic features of 9 cases. Blood 2009. 114: 638-646. http://dx.doi.org/10.1182/blood-2008-12-196568 PMid:19387007
53. Dal-Bo, M., Del Giudice, I., Bomben, R., Capello, D., Bertoni, F., Forconi, F., Laurenti, L., Rossi, D., Zucchetto, A., Pozzato, G., Marasca, R., Efremov, D. G., Guarini, A., Del Poeta, G., Foa, R., Gaidano, G. and Gattei, V., B-cell receptor, clinical course and prognosis in chronic lymphocytic leukaemia: the growing saga of the IGHV3 subgroup gene usage. Br J Haematol 2011. 153: 3-14. http://dx.doi.org/10.1111/j.1365-2141.2010.08440.x PMid:21303354
54. Thorselius, M., Krober, A., Murray, F., Thunberg, U., Tobin, G., Buhler, A., Kienle, D., Albesiano, E., Maffei, R., Dao-Ung, L. P., Wiley, J., Vilpo, J., Laurell, A., Merup, M., Roos, G., Karlsson, K., Chiorazzi, N., Marasca, R., Dohner, H., Stilgenbauer, S. and Rosenquist, R., Strikingly homologous immunoglobulin gene rearrangements and poor outcome in VH3-21-using chronic lymphocytic leukemia patients independent of geographic origin and mutational status. Blood 2006. 107: 2889-2894. http://dx.doi.org/10.1182/blood-2005-06-2227 PMid:16317103
55. Oscier, D., Wade, R., Davis, Z., Morilla, A., Best, G., Richards, S., Else, M., Matutes, E. and Catovsky, D., Prognostic factors identified three risk groups in the LRF CLL4 trial, independent of treatment allocation. Haematologica 2010. 95: 1705-1712. http://dx.doi.org/10.3324/haematol.2010.025338 PMid:20511662 PMCid:2948096
56. Ghiotto, F., Fais, F., Valetto, A., Albesiano, E., Hashimoto, S., Dono, M., Ikematsu, H., Allen, S. L., Kolitz, J., Rai, K. R., Nardini, M., Tramontano, A., Ferrarini, M. and Chiorazzi, N., Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia. J Clin Invest 2004. 113: 1008-1016. PMid:15057307 PMCid:379317
57. Rossi, D., Spina, V., Cerri, M., Rasi, S., Deambrogi, C., De Paoli, L., Laurenti, L., Maffei, R., Forconi, F., Bertoni, F., Zucca, E., Agostinelli, C., Cabras, A., Lucioni, M., Martini, M., Magni, M., Deaglio, S., Ladetto, M., Nomdedeu, J. F., Besson, C., Ramponi, A., Canzonieri, V., Paulli, M., Marasca, R., Larocca, L. M., Carbone, A., Pileri, S. A., Gattei, V. and Gaidano, G., Stereotyped B-cell receptor is an independent risk factor of chronic lymphocytic leukemia transformation to Richter syndrome. Clin Cancer Res 2009. 15: 4415-4422. http://dx.doi.org/10.1158/1078-0432.CCR-08-3266 PMid:19509140
58. Ghia, P., Stamatopoulos, K., Belessi, C., Moreno, C., Stella, S., Guida, G., Michel, A., Crespo, M., Laoutaris, N., Montserrat, E., Anagnostopoulos, A., Dighiero, G., Fassas, A., Caligaris-Cappio, F. and Davi, F., Geographic patterns and pathogenetic implications of IGHV gene usage in chronic lymphocytic leukemia: the lesson of the IGHV3-21 gene. Blood 2005. 105: 1678-1685. http://dx.doi.org/10.1182/blood-2004-07-2606 PMid:15466924
59. Potter, K. N., Mockridge, C. I., Neville, L., Wheatley, I., Schenk, M., Orchard, J., Duncombe, A. S., Packham, G. and Stevenson, F. K., Structural and functional features of the B-cell receptor in IgG-positive chronic lymphocytic leukemia. Clin Cancer Res 2006. 12: 1672-1679. http://dx.doi.org/10.1158/1078-0432.CCR-05-2164 PMid:16551848
60. Sutton, L. A., Kostareli, E., Hadzidimitriou, A., Darzentas, N., Tsaftaris, A., Anagnostopoulos, A., Rosenquist, R. and Stamatopoulos, K., Extensive intraclonal diversification in a subgroup of chronic lymphocytic leukemia patients with stereotyped IGHV4-34 receptors: implications for ongoing interactions with antigen. Blood 2009. 114: 4460-4468. http://dx.doi.org/10.1182/blood-2009-05-221309 PMid:19713457
61. Kostareli, E., Sutton, L. A., Hadzidimitriou, A., Darzentas, N., Kouvatsi, A., Tsaftaris, A., Anagnostopoulos, A., Rosenquist, R. and Stamatopoulos, K., Intraclonal diversification of immunoglobulin light chains in a subset of chronic lymphocytic leukemia alludes to antigen-driven clonal evolution. Leukemia 2010. 24: 1317-1324. http://dx.doi.org/10.1038/leu.2010.90 PMid:20463750
62. Broker, B. M., Klajman, A., Youinou, P., Jouquan, J., Worman, C. P., Murphy, J., Mackenzie, L., Quartey-Papafio, R., Blaschek, M., Collins, P. and et al., Chronic lymphocytic leukemic (CLL) cells secrete multispecific autoantibodies. J Autoimmun 0988. 1: 469-481. http://dx.doi.org/10.1016/0896-8411(88)90068-6
63. Sthoeger, Z. M., Wakai, M., Tse, D. B., Vinciguerra, V. P., Allen, S. L., Budman, D. R., Lichtman, S. M., Schulman, P., Weiselberg, L. R. and Chiorazzi, N., Production of autoantibodies by CD5-expressing B lymphocytes from patients with chronic lymphocytic leukemia. J Exp Med 0989. 169: 255-268. http://dx.doi.org/10.1084/jem.169.1.255 PMid:2462608
64. Borche, L., Lim, A., Binet, J. L. and Dighiero, G., Evidence that chronic lymphocytic leukemia B lymphocytes are frequently committed to production of natural autoantibodies. Blood 0990. 76: 562-569. PMid:2378986
65. Hatzi, K., Catera, R., Ferrarini, M., Fischetti, V., Herve, M., Meffre, E., Chu, C. C. and Chiorazzi, N., B-Cell Chronic Lymphocytic Leukemia (B-CLL) Cells Express Antibodies Reactive with Antigenic Epitopes Expressed on the Surface of Common Bacteria. Blood (ASH Annual Meeting Abstracts) 2006. 108: Abstract 25.
66. Seiler, T., Woelfle, M., Yancopoulos, S., Catera, R., Li, W., Hatzi, K., Moreno, C., Torres, M., Paul, S., Dohner, H., Stilgenbauer, S., Kaufman, M. S., Kolitz, J. E., Allen, S. L., Rai, K. R., Chu, C. C. and Chiorazzi, N., Characterization of structurally defined epitopes recognized by monoclonal antibodies produced by chronic lymphocytic leukemia B cells. Blood 2009. 114: 3615-3624. http://dx.doi.org/10.1182/blood-2009-01-197822 PMid:19690339 PMCid:2858644
67. Goodyear, C. S. and Silverman, G. J., B cell superantigens: a microbe's answer to innate-like B cells and natural antibodies. Springer Semin Immunopathol 2005. 26: 463-484. http://dx.doi.org/10.1007/s00281-004-0190-2 PMid:15633015
68. Baumgarth, N., Tung, J. W. and Herzenberg, L. A., Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion. Springer Semin Immunopathol 2005. 26: 347-362. http://dx.doi.org/10.1007/s00281-004-0182-2 PMid:15633017
69. Schwartz-Albiez, R., Monteiro, R. C., Rodriguez, M., Binder, C. J. and Shoenfeld, Y., Natural antibodies, intravenous immunoglobulin and their role in autoimmunity, cancer and inflammation. Clin Exp Immunol 2009. 158 Suppl 1: 43-50. http://dx.doi.org/10.1111/j.1365-2249.2009.04026.x
70. Binder, M., Lechenne, B., Ummanni, R., Scharf, C., Balabanov, S., Trusch, M., Schluter, H., Braren, I., Spillner, E. and Trepel, M., Stereotypical chronic lymphocytic leukemia B-cell receptors recognize survival promoting antigens on stromal cells. PLoS One 2010. 5: e15992. http://dx.doi.org/10.1371/journal.pone.0015992 PMid:21209908 PMCid:3012720
71. Stamatopoulos, K., Antigens in CLL: themes and variations. Blood 2010. 115: 3855-3856. http://dx.doi.org/10.1182/blood-2010-02-270249 PMid:20466865
72. Binder, C. J., Horkko, S., Dewan, A., Chang, M. K., Kieu, E. P., Goodyear, C. S., Shaw, P. X., Palinski, W., Witztum, J. L. and Silverman, G. J., Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med 2003. 9: 736-743. http://dx.doi.org/10.1038/nm876 PMid:12740573
73. Landgren, O., Rapkin, J. S., Caporaso, N. E., Mellemkjaer, L., Gridley, G., Goldin, L. R. and Engels, E. A., Respiratory tract infections and subsequent risk of chronic lymphocytic leukemia. Blood 2007. 109: 2198-2201. http://dx.doi.org/10.1182/blood-2006-08-044008 PMid:17082317 PMCid:1801057
74. Kostareli, E., Hadzidimitriou, A., Stavroyianni, N., Darzentas, N., Athanasiadou, A., Gounari, M., Bikos, V., Agathagelidis, A., Touloumenidou, T., Zorbas, I., Kouvatsi, A., Laoutaris, N., Fassas, A., Anagnostopoulos, A., Belessi, C. and Stamatopoulos, K., Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors. Leukemia 2009. 23: 919-924. http://dx.doi.org/10.1038/leu.2008.379 PMid:19148139
75. Steininger, C., Rassenti, L. Z., Vanura, K., Eigenberger, K., Jager, U., Kipps, T. J., Mannhalter, C., Stilgenbauer, S. and Popow-Kraupp, T., Relative seroprevalence of human herpes viruses in patients with chronic lymphocytic leukaemia. Eur J Clin Invest 2009. 39: 497-506. http://dx.doi.org/10.1111/j.1365-2362.2009.02131.x PMid:19490058
76. Steininger, C., Widhopf, G. F., 2nd, Ghia, E. M., Morello, C. S., Vanura, K., Sanders, R., Spector, D., Guiney, D., Jager, U. and Kipps, T. J., Recombinant antibodies encoded by IGHV1-69 react with pUL32, a phosphoprotein of cytomegalovirus and B-cell superantigen. Blood 2012. 119: 2293-2301. http://dx.doi.org/10.1182/blood-2011-08-374058 PMid:22234695
77. Kostareli, E., Gounari, M., Janus, A., Murray, F., Brochet, X., Giudicelli, V., Pospisilova, S., Oscier, D., Foroni, L., di Celle, P. F., Tichy, B., Pedersen, L. B., Jurlander, J., Ponzoni, M., Kouvatsi, A., Anagnostopoulos, A., Thompson, K., Darzentas, N., Lefranc, M. P., Belessi, C., Rosenquist, R., Davi, F., Ghia, P. and Stamatopoulos, K., Antigen receptor stereotypy across B-cell lymphoproliferations: the case of IGHV4-59/IGKV3-20 receptors with rheumatoid factor activity. Leukemia. 2012 May;26(5):1127-31. doi: 10.1038/leu.2011.311 http://dx.doi.org/10.1038/leu.2011.311 PMid:22051533
78. Scharenberg, A. M., Humphries, L. A. and Rawlings, D. J., Calcium signalling and cell-fate choice in B cells. Nat Rev Immunol 2007. 7: 778-789. http://dx.doi.org/10.1038/nri2172 PMid:17853903 PMCid:2743935
79. Suljagic, M., Longo, P. G., Bennardo, S., Perlas, E., Leone, G., Laurenti, L. and Efremov, D. G., The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Emu- TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling. Blood 2010. 116: 4894-4905. http://dx.doi.org/10.1182/blood-2010-03-275180 PMid:20716772
80. Song, Z., Lu, P., Furman, R. R., Leonard, J. P., Martin, P., Tyrell, L., Lee, F. Y., Knowles, D. M., Coleman, M. and Wang, Y. L., Activities of SYK and PLCgamma2 predict apoptotic response of CLL cells to SRC tyrosine kinase inhibitor dasatinib. Clin Cancer Res 2010. 16: 587-599. http://dx.doi.org/10.1158/1078-0432.CCR-09-1519 PMid:20068106
81. Schattner, E. J., CD40 ligand in CLL pathogenesis and therapy. Leuk Lymphoma 2000. 37: 461-472. http://dx.doi.org/10.3109/10428190009058499
82. Grdisa, M., Influence of CD40 ligation on survival and apoptosis of B-CLL cells in vitro. Leuk Res 2003. 27: 951-956. http://dx.doi.org/10.1016/S0145-2126(03)00028-6
83. Granziero, L., Ghia, P., Circosta, P., Gottardi, D., Strola, G., Geuna, M., Montagna, L., Piccoli, P., Chilosi, M. and Caligaris-Cappio, F., Survivin is expressed on CD40 stimulation and interfaces proliferation and apoptosis in B-cell chronic lymphocytic leukemia. Blood 2001. 97: 2777-2783. http://dx.doi.org/10.1182/blood.V97.9.2777 PMid:11313271
84. Scielzo, C., Apollonio, B., Scarfo, L., Janus, A., Muzio, M., Ten Hacken, E., Ghia, P. and Caligaris-Cappio, F., The functional in vitro response to CD40 ligation reflects a different clinical outcome in patients with chronic lymphocytic leukemia. Leukemia 2011. 25: 1760-1767. http://dx.doi.org/10.1038/leu.2011.149 PMid:21709686