Multiple Myeloma Clones are Derived from a Cell Late in B Lymphoid Development

  • J. R. Berenson
  • R. A. Vescio
  • C. H. Hong
  • J. Cao
  • A. Kim
  • C. C. Lee
  • G. Schiller
  • R. J. Berenson
  • A. K. Lichtenstein
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 194)


We have previously demonstrated that the immunoglobulin (Tg) heavy chain variable region (VH) sequences expressed by the malignant clone in multiple myeloma (MM) contain a high degree of somatic mutation without clonal diversity. This sequence can be used to identify all members of the malignant clone in this B cell malignancy. We sequenced the variable regions expressed by patients with MM and generated primers from the complementarity determining region (CDR) sequences specific for each patient’s tumor. Using these primers, we performed PCR amplification on highly purified subpopulations of cells separated by expression of CD 10, CD34 and CD38. The results of these experiments demonstrate: 1) there is a small fraction of CDlO-expressing tumor cells in MM patients, 2) CD34-bearing malignant cells do not exist in MM, and 3) although the vast amount of tumor is in the CD38-expressing cells, a small amount of tumor is in the CD38-negative population. We also used these primers to determine whether pre-class switch (i.e., Cµ.-expressing lymphocytes) clonal cells exist in these patients. After PCR amplification with CDR1 and Cµ primers, colony hybridization was performed using both framework 3 (FR3) and CDR3 probes. Out of >200 FR3-hybridizing colonies, ≤ 5 colonies also hybridized with the CDR3 probe. Colonies which hybridized with both these probes were sequenced, and none of these sequences matched even closely the CDR3 expressed by the malignant clone. These results make the existence of a pre-class switch malignant cell unlikely in MM. Overall, these results suggest that the malignant clone in MM derives from a cell late in B lymphocyte development.


mUltiple Myeloma Bone Marrow Mononuclear Cell Complementarity Determine Region Colony Hybridization Malignant Plasma Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Vescio RA, Cao J, Hong CH, Newman R, Lichtenstein AK, Berenson JR (1994) Somatic hypermutation of VH genes in multiple myeloma is unaccompanied by intraclonal diversity. Blood 82 (suppl. I): 259aGoogle Scholar
  2. 2.
    Epstein JH, Xiano-Yan H (1990) Markers of multiple hematopoietic-cell lineages in multiple myeloma. N Eng J Med 322: 664–668CrossRefGoogle Scholar
  3. 3.
    Cuzick J, Erskine S, Edelman D, Galton DAG (1987) A comparison of the incidence of the myelodysplastic syndrome and acute myeloid leukemia following melphalan and cyclophosphamide treatment for myelomatosis. Br J Cancer 55: 523–529PubMedCrossRefGoogle Scholar
  4. 4.
    Kubagawa H, Vogler LB, Capra JD, Conrad ME, Lawton AR, Cooper MD (1979) Use of individually specific (idiotype) antibodies to trace the oncogenic event to its earliest point in B-cell differentiation. J Exp Med 150: 792–807PubMedCrossRefGoogle Scholar
  5. 5.
    Billadeau D, Ahmann G, Greipp P, Van Ness B (1993) 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 178: 1023–1030PubMedCrossRefGoogle Scholar
  6. 6.
    Corradini P, Boccadoro M, Voena C, Pileri A (1993) Evidence for a bone marrow B cell transcribing malignant plasma cell VDJ joined to C mu sequence in immunoglobulin ( IgG)- and IgA-secreting multiple meylomas. J Exp Med 178: 1091–1096PubMedCrossRefGoogle Scholar
  7. 7.
    Vesole DH, Jagannath S, Glenn L, Barlogie B (1993) Autotransplantation in multiple myeloma. Hematology/Oncology Clinics of North America 7: 613–630PubMedGoogle Scholar
  8. 8.
    Berenson JR, Wong R, Kim K, Brown N, Lichtenstein A (1987) Evidence for perippheral blood B lymphocyte but not T lymphocyte involvement in multiple myeloma. Blood 70: 1550–1553PubMedGoogle Scholar
  9. 9.
    Billadeau D, Quam L, Thomas W, Greipp P, Kyle R, Oken MM, Van Ness B (1992) Detection and quantitation of malignant cells in the peripheral blood of multiple myeloma patients. Blood 80: 1818–1824PubMedGoogle Scholar
  10. 10.
    Shpall E, Jones RB, Franklin RB, et al. (1994) Transplantation of enriched CD34-positive autologous marrow into breast cancer patients following high-dose chemotherapy: Influence of CD34-positive periphral-blood progenitors and growth factors on engraftment. J Clin Onco 12: 28–36Google Scholar
  11. 11.
    Scmitt C, Eaves CJ, Lansdorp PPM (1991) Expression of CD34 on B cell precursors. Clin Exp Immunol 85: 168–173CrossRefGoogle Scholar
  12. 12.
    Terstappen LWMM, Johnsen S, Segers-Nolten IMJ, Loken MR (1990) Identification and characterization of plasma cells in normal human bone marrow by high-resolution flow cytometry. Blood 76: 1739–1747PubMedGoogle Scholar
  13. 13.
    Kawano MM, Huang N, Harada H, Harada Y, Sakai A, Tanaka H, Iwato K, Kuramoto A (1993) Identification of immature and mature myeloma cells in the bone marrow of human myelomas. Blood 82: 564–570PubMedGoogle Scholar
  14. 14.
    Sato N, Sawada K, Koizumi K, et al. (1993) In vitro expansion of human peripheral blood CD34+ cells. Blood 82: 3600–3609PubMedGoogle Scholar
  15. 15.
    Brown G, Hogg N, Greaves M (1975) Candidate leukemia-specific antigen in man. Nature 258: 454–456PubMedCrossRefGoogle Scholar
  16. 16.
    Greaves MF, Hairi F, Newman RA, Sutherland DR, Ritter MA, Ritz J (1983) Selective expression of the common acute lymphoblastic leukemia (gplOO) antigen on immature lymphoid cells and their malignant counterparts. Blood 61: 628–639PubMedGoogle Scholar
  17. 17.
    Hsu SM, Jaffe ES (1984) Phenotypic expression of B-lymphocytes. 1. Identification with monoclonal antibodies in normal lymphoid tissues. Am J Pathol 114: 387–395PubMedGoogle Scholar
  18. 18.
    Cossman J, Neckers LM, Leonard WJ, Greene WC (1983) Polymorphonuclear neutrophils express the common acute lymphoblastic leukemia antigen. J Exp Med 157: 1064–1069PubMedCrossRefGoogle Scholar
  19. 19.
    Metzgar RS, Borowitz MJ, Jones NH, Dowell BL (1981) Distribution of common acute lymphoblastic leukemia antigen in non-hematopoietic tissues. J Exp Med 154: 1249–1254PubMedCrossRefGoogle Scholar
  20. 20.
    Warburton P, Joshua DE, Gibson J, Brown RD (1989) CD10-(CALLA)-positive lymphocytes in myeloma: Evidence that they are a malignant precursor population and are of germinal centre origin. Leukemia and Lymphoma 1: 11–20CrossRefGoogle Scholar
  21. 21.
    Durie BGM, Salmon SE (1975) A clinical staging system for multiple myeloma. Cancer 36: 842–852PubMedCrossRefGoogle Scholar
  22. 22.
    Andrews RG, Singer JW, Bernstein ID (1986) Monoclonal antibody 12.8 recognizes a 115-Kd molecule on both unipotent and multipotent hematopoietic colony-forming cells and their precursors. Blood 67: 842–845PubMedGoogle Scholar
  23. 23.
    Drexler HG, Thiel E, Ludwig W-D (1993) Acute myeloid leukemias expressing lymphoid-associated antigens: Diagnostic incidence and prognostic significance Leukemia 7: 489–498Google Scholar
  24. 24.
    Can’t-Rajnoldi A, Putti C, Saitta M, et al. (1991) Co-expression of myeloid antigens in childhood acute lymphoblastic leukaemia: relationship with stage of differentiation and clinical significance. Brit J Haematol 79: 40–43CrossRefGoogle Scholar
  25. 25.
    Berenson JR, Hart S, Cao J, et al. (1991) Expression of shared idiotypes and VH gene families by patients with monoclonal gammopathies. in the Third International Workshop on Myeloma, pp 31–32Google Scholar
  26. 26.
    Kunkel LA, Vescio R, Cao J, Schiller GJ, Lichtenstein AK, Berenson JR (1993) The CDR3 regions of multiple myeloma patients reveal characteristics seen in fetal lymphoid development. Blood 82 (suppl I): 259aGoogle Scholar
  27. 27.
    Stevenson FK, Bell AJ, Cusack R, et al. (1991) Preliminary studies for an immunotherapeutic approach to the treatment of human myeloma using chimeric anti-CD38 antibody. Blood 77: 1071–1079PubMedGoogle Scholar
  28. 28.
    Caligaris-Cappio F, Bergui F, Tesio L, et al. (1985) Identification of malignant plasma cell precursors in the bone marrow of multiple myeloma. J Clin Invest 76: 1243–1251PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • J. R. Berenson
    • 1
  • R. A. Vescio
    • 1
  • C. H. Hong
    • 1
  • J. Cao
    • 1
  • A. Kim
    • 1
  • C. C. Lee
    • 1
  • G. Schiller
    • 1
  • R. J. Berenson
    • 2
  • A. K. Lichtenstein
    • 1
  1. 1.Divisions of Hematology/Oncology, D.V.A. West Los Angeles and UCLA School of MedicineJonsson Comprehensive Cancer CenterLos AngelesUSA
  2. 2.CellPro IncorporatedSuite 100 BothellUSA

Personalised recommendations