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Origin and diversification of the clonogenic cell in multiple myeloma: lessons from the immunoglobulin repertoire

Leukemia volume 14, pages 1718–1726 (2000)Cite this article

Abstract

The study of immunoglobulin genes in multiple myeloma over the last decade has provided important information regarding biology, ontogenetic assignment, disease evolution, pathogenic consequences and tumor-specific therapeutic intervention. Detailed analysis of VH genes has revealed the clonal relationship between switch variants expressed by the bone marrow plasma cell and myeloma progenitors in the marrow and peripheral blood. Regarding VH usage, a bias was found against the V4-34 gene encoding antibodies with cold agglutinin specificity (anti-l/i), thus explaining in part the absence of autoimmune phenomena in myeloma compared to other B cell lymphoproliferative disorders. However, in some studies a substantial number of cases analyzed were carrying the rearranged Humκv325 Vκ gene, known to be over utilized by B cell chronic lymphocytic leukemia clones and possessing autoantibody binding activity. VH genes accumulate somatic hypermutations following a distribution compatible with antigen selection, but with no intraclonal heterogeneity. The analysis of Vκ genes indicates a bias in usage of VκI family members; somatic hypermutation, in line with antigen selection, of the expressed Vκ genes is higher than any other B cell lymphoid disorder. Similar conclusions were reached for Vλ genes; in this case, the analysis raises the controversial issue of N nucleotide insertion at Vλ–Jλ junctions, apparently as a result of TdT activity. A complementary imprint of antigen selection as evidenced by somatic hypermutation of either the VH or VL clonogenic genes has been observed. The absence of ongoing somatic mutations in either VH or VL genes gives rise to the notion that the cell of origin in myeloma is a post-germinal center memory B cell.

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References

  1. Epstein J, Xiao H, He XY . Markers of multiple hematopoietic stem cell lineages in multiple myeloma New Engl J Med 1990 322: 664–668

    Article  CAS  PubMed  Google Scholar 

  2. Teoh G, Anderson KC . Interaction of tumor and host cells with adhesion and extracellular matrix molecules in the development of multiple myeloma Hematol Oncol Clin North Am 1997 11: 27–42

    Article  CAS  PubMed  Google Scholar 

  3. Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Nunez G, Dalton WS, Jove R . Constitutive activation of Stat3 signaling confers resistance to apoptosis in human myeloma tumor cells Immunity 1999 10: 105–115

    Article  CAS  PubMed  Google Scholar 

  4. Landowski TH, Qu N, Buyuksal I, Painter JS, Dalton WS . Mutations in the Fas antigen in patients with multiple myeloma Blood 1997 90: 4266–4270

    CAS  PubMed  Google Scholar 

  5. Rettig MA, Ma HJ, Vescio RA, Põld M, Schiller G, Belson D, Savage A, Nishikubo C, Wu C, Fraser J, Said JW, Berenson JR . Kaposi's sarcoma-associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients Science 1997 276: 1851–1854

    Article  CAS  PubMed  Google Scholar 

  6. Cull GM, Timm S, Haynes A, Russell N, Irvig W, Ball J, Thomson B . Dendritic cells cultured from mononuclear cells and CD34 cells in myeloma do not harbour human herpesvirus 8 Br J Haematol 1998 100: 793–796

    Article  CAS  PubMed  Google Scholar 

  7. Yi Q, Ekman M, Anton D, Bergenbrant B, Osterborg A, Georgii-Hemming P, Holm G, Nilsson K, Biberfield P . Blood dendritic cells from myeloma patients are not infected with Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) Blood 1998 92: 402–404

    CAS  PubMed  Google Scholar 

  8. van Noesel CJM, van Lier RAW . Architecture of the human B-cell antigen receptors Blood 1993 82: 363–373

    CAS  PubMed  Google Scholar 

  9. Chuchana P, Blancer A, Brockly F, Alexandre D, Lefranc G, Lefranc MP . Definition of the human immunoglobulin variable lambda gene subgroups Eur J Immunol 1990 20: 1317–1325

    Article  CAS  PubMed  Google Scholar 

  10. Walter MA, Surti U, Hofker MH, Cox DW . The physical organization of the human immunoglobulin heavy chain gene EMBO J 1990 9: 3303–3313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Klein R, Jaenichen R, Zachau HG . Expressed human immunoglobulin κ genes and their hypermutation Eur J Immunol 1993 23: 3248–3262

    Article  CAS  PubMed  Google Scholar 

  12. Korsmeyer SJ, Hieter PA, Ravetch JV, Poplack DG, Waldmann TA, Leder P . Developmental hierarchy of immunoglobulin gene rearrangements in human leukemic pre-B-cells Proc Natl Acad Sci USA 1981 78: 7096–7100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Reth M, Petrac E, Wiese P, Lobel L, Alt FW . Activation of Vκ gene rearrangement in pre-B cells follows the expression of membrane-bound immunoglobulin heavy chains EMBO J 1987 6: 3299–3305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Takemori T, Rajewsky K . Lambda chain expression at different stages of ontogeny in C57BL/6, BALB/c and SJL mice Eur J Immunol 1981 11: 618–625

    Article  CAS  PubMed  Google Scholar 

  15. Ehlich A, Schaal S, Gu H, Kitamura D, Müller W, Rajewsky K . Immunoglobulin heavy and light chain genes rearrange independently at early stages of B-cell development Cell 1993 72: 695–704

    Article  CAS  PubMed  Google Scholar 

  16. Pauza ME, Rehmann JA, LeBien TW . Unusual patterns of immunoglobulin gene rearrangement and expression during human B-cell ontogeny: human B-cells can simultaneously express cell surface κ and λ light chains J Exp Med 1993 178: 139–149

    Article  CAS  PubMed  Google Scholar 

  17. Betz AG, Rada C, Pannell R, Milstein C, Neuberger MS . Passenger transgenes reveal intrinsic specificity of the antibody hypermutation mechanism: clustering, polarity, and specific hot spots Proc Natl Acad Sci USA 1993 90: 2385–2388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nossal GJV . Negative selection of lymphocytes Cell 1994 76: 229–239

    Article  CAS  PubMed  Google Scholar 

  19. Vescio R, Hong CH, Cao J, Kim A, Schiller GJ, Lichtenstein A, Berenson R, Berenson J . The hematopoietic stem cell antigen, CD34, is not expressed on the malignant cells in multiple myeloma Blood 1994 84: 3283–3290

    CAS  PubMed  Google Scholar 

  20. Gazitt Y, Reading CC, Hoffman R, Wickrema A, Vesole D, Jagannath S, Condino J, Lee B, Barlogie B, Tricot G . Purified CD34+Lin−Thy+ stem cells do not contain clonal myeloma cells Blood 1995 86: 381–389

    CAS  PubMed  Google Scholar 

  21. Kimlinger T, Witzig TE . Expression of the hematopoietic stem cell antigen CD34 on blood and bone marrow monoclonal plasma cells from patients with multiple myeloma Bone MarrowTransplant 1997 19: 553–556

    CAS  Google Scholar 

  22. Szczepek AJ, Bergsagel PL, Axelsson L, Brown CB, Belch AR, Pilarski LM . CD34+ cells in the blood of patients with multiplemyeloma express CD19 and Ig mRNA and have patient-specific IgH VDJ gene rearrangements Blood 1997 89: 1824–1833

    CAS  PubMed  Google Scholar 

  23. Witzig TE, Dhodapkar MV, Kyle RA, Greipp PR . Quantification of circulating peripheral blood plasma cells and their relationship to disease activity in patients with multiple myeloma Cancer 1993 72: 108–113

    Article  CAS  PubMed  Google Scholar 

  24. Billadeau D, Ahman G, Greipp P, Van Ness B . The bone marrow of multiple myeloma patients contains B-cell populations at different stages of differentiation that are clonally related to the malignant plasma cell J Exp Med 1993 178: 1023–1031

    Article  CAS  PubMed  Google Scholar 

  25. Corradini P, Boccadoro M, Voena C, Pileri A . Evidence for a bone marrow B cell transcribing malignant plasma cell VDJ joined to Cμ sequence in immunoglobulin (IgG)- and IgA-secreting multiple myelomas J Exp Med 1993 178: 1091–1096

    Article  CAS  PubMed  Google Scholar 

  26. Bakkus MHC, Van Riet I, Van Camp B, Thielemans K . Evidence that the clonogenic cell in multiple myeloma originates from a pre-switched but somatically mutated B cell Br J Haematol 1994 87: 68–74

    Article  CAS  PubMed  Google Scholar 

  27. Gray D . Immunological memory Annu Rev Immunol 1993 11: 49–77

    Article  CAS  PubMed  Google Scholar 

  28. Bergsagel PL, Chesi M, Nardini E, Brents LA, Kirby SL, Kuehl WM . Promiscuous translocations into immunoglobulin heavy chain switc regions in multiple myeloma Proc Natl Acad Sci USA 1996 93: 13931–13936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chesi M, Nardini E, Brents LA, Schröck E, Ried T, Kuehl WM, Bergsagel PL . Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3 Nat Genet 1997 16: 260–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Iida S, Rao PH, Butler M, Corradini P, Boccadoro M, Klein B, Chaganti RSK, Dalla-Favera R . Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma Nat Genet 1997 17: 226–230

    Article  CAS  PubMed  Google Scholar 

  31. Chesi M, Bergsagel PL, Shonukan OO, Martelli ML, Brents LA, Chen T, Schröck E, Ried T, Kuehl WM . Frequent dysregulation of the c-maf proto-oncogene at 16q23 by translocation to an Ig locus in multiple myeloma Blood 1998 91: 4457–4463

    CAS  PubMed  Google Scholar 

  32. Pold M, Rettig M, Munroe D, Vescio R, Hall J, Berenson J . Expression of novel genes in human chromosomal locus 11q13 Blood 1997 90: 317a (Abstr.)

    Google Scholar 

  33. Potter M, Wiener F . Plasmacytomagenesis in mice: model ofneoplastic development dependent upon chromosomaltranslocations Carcinogenesis 1992 13: 1681–1697

    Article  CAS  PubMed  Google Scholar 

  34. Kuehl WM, Brents LA, Chesi M, Huppi K, Bergsagel PL . Dysregulation of c-myc in multiple myeloma Curr Top Microbiol Immunol 1997 224: 277–282

    CAS  PubMed  Google Scholar 

  35. Shou Y, Martelli ML, Gabrea A, Qi Y, Brents LA, Roschke A, Dewald G, Kirsch IR, Bergsagel PL, Kuehl WM . Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma Proc Natl Acad Sci USA 2000 97: 228–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Vescio RA, Cao J, Hong CH, Lee JC, Wu CH, Der-Danielian M, Wu V, Newman R, Lichtenstein AK, Berenson JR . Myeloma Ig heavy chain V region sequences reveal prior antigenic selection and marked somatic mutation but no intraclonal diversity J Immunol 1995 155: 2487–2497

    CAS  PubMed  Google Scholar 

  37. Shlomchik MJ, Marshak-Rothstein A, Wolfowitcz CB, Rothstein TL, Weigert MG . The role of clonal selection and somatic mutation in autoimmunity Nature 1987 328: 805–811

    Article  CAS  PubMed  Google Scholar 

  38. Chang B, Casali P . The CDR1 sequences of a major proportion of human germline lg VH genes are inherently susceptible to amino acid replacement Immunol Today 1994 15: 367–373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kosmas C, Stamatopoulos K, Loukopoulos D . Antigen selection of multiple myeloma clonogenic B cells as evidenced by VH and VL gene mutations Blood 1997 90: 1334–1335

    CAS  PubMed  Google Scholar 

  40. Allen D, Simon T, Sablitzky F, Rajewsky K, Cumano A . Antibody engineering for the analysis of affinity maturation of an anti-hapten response EMBO J 1988 7: 1995–2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sahota SS, Leo R, Hamblin TJ, Stevenson FK . Ig VH gene mutational patterns indicate different tumor cell status in human myeloma and monoclonal gammopathy of undetermined significance Blood 1996 87: 746–755

    CAS  PubMed  Google Scholar 

  42. Avét-Loiseau H, Li J-Y, Morineau N, Facon T, Brigaudeau C, Harousseau J-L, Grosbois B, Bataille R . Monosomy 13 is associated with the transition of monoclonal gammopathy of undetermined significance to multiple myeloma Blood 1999 94: 2583–2589

    PubMed  Google Scholar 

  43. Kanzler H, Küppers R, Hansmann M-L, Rajewsky K . Hodgkin's and Reed–Sternberg cells in Hodgkin's disease represent the outgrowth of a dominant tumor clone derived from (crippled) germinal center B cells J Exp Med 1996 184: 1495–1505

    Article  CAS  PubMed  Google Scholar 

  44. Rettig MA, Vescio RA, Cao J, Wu CH, Lee JC, Han E, DerDanielian M, Newman R, Hong C, Lichtenstein AK, Berenson JR . VH gene usage in multiple myeloma: complete abscence of the VH4.21 (VH4–34) gene Blood 1996 87: 2846–2852

    CAS  PubMed  Google Scholar 

  45. Deane M, Baker BW, Norton JD . Immunoglobulin VH4 gene usage in B lymphoid leukaemias Br J Haematol 1993 84: 242–249

    Article  CAS  PubMed  Google Scholar 

  46. Pritsch O, Magnac C, Dumas G, Egile C, Dighiero G . V gene usage by seven hybrids derived from CD5+ B-cell chronic lymphocytic leukemia and displaying autoantibody activity Blood 1993 82: 3103–3112

    CAS  PubMed  Google Scholar 

  47. Maloum K, Magnac C, Pritsch O, Binet JL, Merle-Béral H, Dighiero G . Skewed rearrangement of the VH 4–21 gene during pre-B acute lymphoblastic leukemia Leuk Lymphoma 1995 17: 435–441

    Article  CAS  PubMed  Google Scholar 

  48. Hsu FJ, Levy R . Preferential use of the VH4 Ig gene family by diffuse large-cell lymphoma Blood 1995 86: 3072–3082

    CAS  PubMed  Google Scholar 

  49. Pascual V, Victor K, Spellerberg M, Hamblin TJ, Stevenson FK, Capra JD . VH restriction among human cold agglutinins. The VH 4–21 gene segment is required to encode anti-I and anti-i specificities J Immunol 1992 149: 2337–2344

    CAS  PubMed  Google Scholar 

  50. Kosmas C, Viniou NA, Stamatopoulos K, Courtenay-Luck NS, Papadaki T, Kollia P, Paterakis G, Anagnostou D, Yataganas X, Loukopoulos D . Analysis of κ light chain variable region in multiple myeloma Br J Haematol 1996 94: 306–317

    Article  CAS  PubMed  Google Scholar 

  51. Wagner SD, Martinelli V, Luzzatto L . Similar patterns of Vκ gene usage but different degrees of somatic mutation in hairy cell leukemia, prolymphocytic leukemia, Waldenström's macroglobulinemia, and myeloma Blood 1994 83: 3647–3653

    CAS  PubMed  Google Scholar 

  52. Cannell PK, Amlot P, Attard M, Hoffbrand AV, Foroni L . Variable κ gene rearrangement in lymphoproliferative disorders and analysis of Vκ gene usage, VJ joining and somatic mutation Leukemia 1994 8: 1139–1145

    CAS  PubMed  Google Scholar 

  53. Sahota SS, Leo R, Hamblin TJ, Stevenson FK . Myeloma VL and VH sequences reveal a complementary imprint of antigen selection in tumor cells Blood 1997 89: 219–226

    CAS  PubMed  Google Scholar 

  54. Kiyoi H, Naito K, Ohno R, Saito H, Naoe T . Characterization of the immunoglobulin light chain variable region gene expressed in multiple myeloma Leukemia 1998 12: 601–609

    Article  CAS  PubMed  Google Scholar 

  55. Cuisinier AM, Fumoux D, Moinier D, Boubli L, Guigou V, Milili M, Schiff C, Fougereau M, Tonelle C . Rapid expansion of human immunoglobulin repertoire (VH, Vκ, Vλ) expressed in early fetal bone marrow New Biologist 1990 2: 689–699

    CAS  PubMed  Google Scholar 

  56. Rassenti LZ, Pratt LF, Chen PP, Carson DA, Kipps TJ . Autoantibody-encoding κ L chain genes frequently rearranged in λ L chain-expressing chronic lymphocytic leukemia J Immunol 1991 147: 1060–1066

    CAS  PubMed  Google Scholar 

  57. Kosmas C, Stamatopoulos K, Papadaki T, Belessi C, Yataganas X, Anagnostou D, Loukopoulos D . Somatic hypermutation of immunoglobulin genes: focus on follicular lymphoma and multiple myeloma Immunol Rev 1998 162: 281–292

    Article  CAS  PubMed  Google Scholar 

  58. Stiernholm NBJ, Kuzniar B, Berinstein NL . Identification of a new human Vλ gene family-VλX J Immunol 1994 152: 4969–4975

    CAS  PubMed  Google Scholar 

  59. Boudinot P, Drapier A-M, Cazenave P-A, Sanchez P . Mechanistic and selective constraints act on the establishment of VλJλ junctions in the B cell repertoire J Immunol 1994 152: 2248–2255

    CAS  PubMed  Google Scholar 

  60. Farner NL, Dörner T, Lipsky PE . Molecular mechanisms and selection influence the generation of the human Vλ–Jλ gene repertoire J Immunol 1999 162: 2137–2145

    CAS  PubMed  Google Scholar 

  61. Zheng B, Han S, Spanopoulou E, Kelsoe G . Immunoglobulin gene hypermutation in germinal centers is independent of the RAG-1 V(D)J recombinase Immunol Rev 1998 162: 133–141

    Article  CAS  PubMed  Google Scholar 

  62. Liu YJ, de Bouteiller O, Arpin C, Brière F, Galibert L, Ho S, Martinez-Valdez H, Banchereau J, Lebeque S . Normal human IgD+ IgM− germinal center B cells can express up to 80 mutations in the variable region of their IgD transcripts Immunity 1996 4: 603–613

    Article  CAS  PubMed  Google Scholar 

  63. Arpin C, de Bouteiller O, Razanajaona D, Fugier-Vivier I, Brière F, Banchereau J, Lebeque S, Liu YJ . The normal counterpart of IgD myeloma cells in germinal center display extensively mutated Ig VH gene, Cμ-Cδ switch, and λ light chain expression J Exp Med 1998 187: 1169–1178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Storb U . The molecular basis of somatic hypermutation of immunoglobulin genes Curr Opin Immunol 1996 8: 206–214

    Article  CAS  PubMed  Google Scholar 

  65. Falk RH, Comenzo RL, Skinner M . The systemic amyloidoses New Engl J Med 1997 337: 898–909

    Article  CAS  PubMed  Google Scholar 

  66. Stevens FJ, Myatt EA, Chang C-H, Westholm FA, Eulitz M, Weiss DT, Murphy C, Solomon A, Schiffer M . A molecular model for self-assembly of amyloid fibrils: immunoglobulin light chains Biochemistry 1995 34: 10697–10702

    Article  CAS  PubMed  Google Scholar 

  67. Solomon A, Frangione B, Franklin EC . Bence Jones proteins and light chains of immunoglobulins: preferential association of the V lambda VI subgroup of human light chains with amyloidosis AL (lambda) J Clin Invest 1982 70: 453–460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Perfetti V, Ubbiali P, Colli Vignarelli M, Diegoli M, Fasani R, Stoppini M, Lisa A, Mangione P, Obici L, Arbustini E, Merlini G . Evidence that amyloidogenic light chains undergo antigen-driven selection Blood 1998 91: 2948–2954

    CAS  PubMed  Google Scholar 

  69. Stamatopoulos K, Kosmas C, Papadaki T, Pouliou E, Belessi C, Afendaki S, Anagnostou D, Loukopoulos D . Follicular lymphoma immunoglobulin κ light chains are affected by the antigen selection process, but to a lesser degree than their partner heavy chains Br J Haematol 1997 96: 132–146

    Article  CAS  PubMed  Google Scholar 

  70. Stamatopoulos K, Kosmas C, Stavroyianni N, Belessi C, Papadaki T . Selection of immunoglobulin diversity gene reading frames in B-cell lymphoproliferative disorders Leukemia 1999 13: 601–604

    Article  CAS  PubMed  Google Scholar 

  71. Stamatopoulos K, Kosmas C, Belessi C, Papadaki T, Afentaki S, Anagnostou D, Loukopoulos D . t(14;18) chromosomal translocation in follicular lymphoma: an event occuring with almost equal frequency both at the D to JH and at later stages in the rearrangement process of the immunoglobulin heavy chain gene locus Br J Haematol 1997 99: 866–872

    Article  CAS  PubMed  Google Scholar 

  72. Stamatopoulos K, Kosmas C, Belessi C, Kyriazopoulos P, Papadaki T, Anagnostou D, Loukopoulos D . Molecular analysis of bcl-1/lgH junctional sequences in mantle cell lymphoma: potential mechanisms of the t(11;14) chromosomal translocation Br J Haematol 1999 105: 190–197

    Article  CAS  PubMed  Google Scholar 

  73. Wagner SD, Milstein C, Neuberger MS . Codon bias targets mutation Nature 1995 376: 732

    Article  CAS  PubMed  Google Scholar 

  74. Goyenechea B, Milstein C . Modifying the sequence of an immunoglobulin V-gene alters the resulting pattern of hypermutation Proc Natl Acad Sci USA 1996 93: 13979–13984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Milstein C, Neuberger MS, Staden R . Both DNA strands of antibody genes are hypermutation targets Proc Natl Acad Sci USA 1998 95: 8791–8794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Neuberger NS, Ehrenstein MR, Klix N, Jolly CJ, Yélamos J, Rada C, Milstein C . Monitoring and interpreting the intrinsic features of somatic hypermutation Immunol Rev 1998 162: 107–116

    Article  CAS  PubMed  Google Scholar 

  77. Goossens T, Klein U, Küppers R . Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy chain disease Proc Natl Acad Sci USA 1998 95: 2463–2468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wilson P, Liu Y-J, Banchereau J, Capra JD, Pascual V . Amino acid insertions and deletions contribute to diversify the human Ig repertoire Immunol Rev 1998 162: 143–151

    Article  CAS  PubMed  Google Scholar 

  79. Rajewsky K . Clonal selection and learning in the antibody system Nature 1996 381: 751–758

    Article  CAS  PubMed  Google Scholar 

  80. Stamatopoulos K, Kosmas C, Belessi C, Stravroyianni N, Kyriazopoulos P, Papadaki T . Molecular insights to the immunopathogenesis of follicular lymphoma Immunol Today 2000 21: 298–305

    Article  CAS  PubMed  Google Scholar 

  81. Billadeau D, Quam I, Thomas W, Kay N, Greipp P, Kyle R, Oken MM . Detection and quantitation of malignant cells in the peripheral blood of multiple myeloma patients Blood 1992 80: 1818–1824

    CAS  PubMed  Google Scholar 

  82. Schiller G, Vescio R, Freytes C, Spitzer G, Sahebi F, Lee M, Wu CH, Cao J, Lee JC, Hong CH, Lichtenstein A, Lill M, Hall J, Berenson R, Berenson J . Transplantation of CD34+ peripheral blood progenitor cells after high-dose chemotherapy for patients with advanced multiple myeloma Blood 1995 86: 390–397

    CAS  PubMed  Google Scholar 

  83. Gianni AM, Tarella C, Bregni M, Siena S, Lombardi F, Gandola L, Caracciolo D, Stern A, Bonadonna G, Boccadoro M, Pileri M . High-dose sequential chemoradiotherapy, a widely applicable regimen, confers survival benefit to patients with high-risk multiple myeloma J Clin Oncol 1994 12: 503–509

    Article  CAS  PubMed  Google Scholar 

  84. Vesole DH, Tricot G, Jagannath S, Desikan KR, Siegel D, Dwayne B, Miller L, Cheson B, Crowley J, Barlogie B . Autotransplants in myeloma: what have we learned Blood 1996 88: 838–847

    CAS  PubMed  Google Scholar 

  85. Corradini P, Voena C, Astolfi M, Ladetto M, Tarella C, Boccadoro M, Pileri S . High-dose sequential chemoradiotherapy in multiple myeloma: residual tumor cells are detectable in bone marrow and peripheral blood cell harvests before and after autografting Blood 1995 85: 1596–1602

    CAS  PubMed  Google Scholar 

  86. Vesole DH, Tricot G, Jagannath S, Desikan KR, Siegel D, Dwayne B, Miller L, Cheson B, Crowley J, Barlogie B . Autotransplants in myeloma: what have we learned Blood 1996 88: 838–847

    CAS  PubMed  Google Scholar 

  87. Björkstrand B, Ljungman P, Bird JM, Samson D, Gahrton G . Double high-dose chemoradiotherapy with autologous stem celltransplantation can induce molecular remissions in multiple myeloma Bone Marrow Transplant 1995 15: 367–371

    PubMed  Google Scholar 

  88. Kwak LW, Campbell MJ, Czerwinski DK, Hart S, Miller RA, Levy R . Induction of immune responses in patients with B cell lymphoma against the surface-immunoglobulin idiotype expressed by their tumors New Engl J Med 1992 327: 1209–1215

    Article  CAS  PubMed  Google Scholar 

  89. Kwak LW, Taub DD, Duffey PL, Bensinger WI, Bryant EM, Reynolds CW, Longo DL . Transfer of myeloma idiotype-specific immunity from an actively immunised marrow donor Lancet 1995 345: 1016–1020

    Article  CAS  PubMed  Google Scholar 

  90. Hawkins RE, Zhu D, Ovecka M, Winter G, Hamblin TJ, Long A, Stevenson FK . Idiotypic vaccination against human B-cell lymphoma. Rescue of variable region gene sequences from biopsy material for assembly as single-chain Fv personal vaccines Blood 1994 83: 3279–3288

    CAS  PubMed  Google Scholar 

  91. Syrengelas AD, Chen TT, Levy R . DNA immunization induces protective immunity against B-cell lymphoma Nature Med 1996 2: 1038–1041

    Article  CAS  PubMed  Google Scholar 

  92. Tao M-H, Levy R . Idiotype/granulocyte–macrophage colony stimulating factor fusion protein as a vaccine for B-cell lymphoma Nature 1993 362: 755–758

    Article  CAS  PubMed  Google Scholar 

  93. Kwak LW . Tumor vaccination strategies combined with autologous peripheral stem cell transplantation Ann Oncol 1998 9: (Suppl. 1) 41–46

    Article  Google Scholar 

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Acknowledgements

CK and KS were supported by grants from the Secretariat for Research and Technology EPET/603 and AXIA 13. NS was supported from the Secretariat for Research and Technology program AXIA 13.

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  1. First Department of Medicine, Athens University School of Medicine, Laikon General Hospital, 21 Apolloniou Street, Athens, 16341, Greece

    C Kosmas, K Stamatopoulos, N Stavroyianni, K Zoi, C Belessi, N Viniou, P Kollia & X Yataganas

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Kosmas, C., Stamatopoulos, K., Stavroyianni, N. et al. Origin and diversification of the clonogenic cell in multiple myeloma: lessons from the immunoglobulin repertoire. Leukemia 14, 1718–1726 (2000). https://doi.org/10.1038/sj.leu.2401908

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