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Evaluating the clonal hierarchy in light-chain multiple myeloma: implications against the myeloma stem cell hypothesis

Leukemia volume 25, pages 1213–1216 (2011)Cite this article

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An exclusive production of light chains can be found in ∼15% of myeloma cases, and in these light-chain multiple myeloma (LC-MM) cases, the phenotype remains unchanged throughout subsequent progression and relapse. Once established, it suggests that this phenotype is maintained by the ‘feeder cell’ that re-populates the tumor bulk as disease re-emerges. This raises an important question of what the nature of the ‘feeder cell’ is that perpetuates disease, a question of wider relevance in multiple myeloma (MM), and how the ‘feeder cell’ is derived from the cell of origin that gives rise to disease.

In defining the cell of origin in MM and other B-cell tumors, immunoglobulin (Ig) variable (IGV) region gene analyses have provided important insights, relying on well-defined events in normal B-cell maturation to establish clonal history. In normal B-cells, IGV assembly occurs early with signature CDR3 motifs1 to constitute functional sIg molecules, allowing exit from the bone marrow (BM). These peripheral B-cells, on recognizing antigen via sIg in secondary lymphoid follicles initiate the germinal center reaction and undergo somatic hypermutation (SHM) of IGV genes. Deletional isotype class switch recombination (CSR) at the chromosome 14q32 locus can also occur in germinal centers to alter effector function.2 IGV analysis can track such events as they relate to malignant B-cell origins.

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References

  1. Alt FW, Blackwell TK, Yancopoulos GD . Development of the primary antibody repertoire. Science (New York, NY ) 1987; 238: 1079–1087.

    Article  CAS  Google Scholar 

  2. Mac Lennan IC . Germinal centers. Annu Rev Immunol 1994; 12: 117–139.

    Article  CAS  Google Scholar 

  3. Stevenson FK, Sahota SS, Ottensmeier CH, Zhu D, Forconi F, Hamblin TJ . The occurrence and significance of V gene mutations in B cell-derived human malignancy. Adv Cancer Res 2001; 83: 81–116.

    Article  CAS  PubMed  Google Scholar 

  4. Szczepanski T, van ‘t Veer MB, Wolvers-Tettero IL, Langerak AW, van Dongen JJ . Molecular features responsible for the absence of immunoglobulin heavy chain protein synthesis in an IgH(-) subgroup of multiple myeloma. Blood 2000; 96: 1087–1093.

    CAS  PubMed  Google Scholar 

  5. Gabrea A, Leif Bergsagel P, Michael Kuehl W . Distinguishing primary and secondary translocations in multiple myeloma. DNA Repair (Amst) 2006; 5: 1225–1233.

    Article  CAS  Google Scholar 

  6. Hose D, Reme T, Meissner T, Moreaux J, Seckinger A, Lewis J et al. Inhibition of aurora kinases for tailored risk-adapted treatment of multiple myeloma. Blood 2009; 113: 4331–4340.

    Article  CAS  PubMed  Google Scholar 

  7. Matsui W, Huff CA, Wang Q, Malehorn MT, Barber J, Tanhehco Y et al. Characterization of clonogenic multiple myeloma cells. Blood 2004; 103: 2332–2336.

    Article  CAS  PubMed  Google Scholar 

  8. Brennan SK, Matsui W . Cancer stem cells: controversies in multiple myeloma. J Mol Med (Berlin, Germany) 2009; 87: 1079–1085.

    Article  Google Scholar 

  9. Huff CA, Matsui W . Multiple myeloma cancer stem cells. J Clin Oncol 2008; 26: 2895–2900.

    Article  PubMed  Google Scholar 

  10. Matsui W, Wang Q, Barber JP, Brennan S, Smith BD, Borrello I et al. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res 2008; 68: 190–197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dick JE . Stem cell concepts renew cancer research. Blood 2008; 112: 4793–4807.

    Article  CAS  PubMed  Google Scholar 

  12. Peacock CD, Wang Q, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci USA 2007; 104: 4048–4053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rasillo A, Tabernero MD, Sanchez ML, Perez de Andres M, Martin Ayuso M, Hernandez J et al. Fluorescence in situ hybridization analysis of aneuploidization patterns in monoclonal gammopathy of undetermined significance versus multiple myeloma and plasma cell leukemia. Cancer 2003; 97: 601–609.

    Article  PubMed  Google Scholar 

  14. Sahota SS, Townsend M, Stevenson FK . Identification and assembly of V genes as idiotype-specific DNA fusion vaccines in multiple myeloma. Method Mol Med 2005; 113: 105–119.

    CAS  Google Scholar 

  15. Forconi F, Sahota SS, Raspadori D, Ippoliti M, Babbage G, Lauria F et al. Hairy cell leukemia: at the crossroad of somatic mutation and isotype switch. Blood 2004; 104: 3312–3317.

    Article  CAS  PubMed  Google Scholar 

  16. Voena C, Ladetto M, Astolfi M, Provan D, Gribben JG, Boccadoro M et al. A novel nested-PCR strategy for the detection of rearranged immunoglobulin heavy-chain genes in B cell tumors. Leukemia 1997; 11: 1793–1798.

    Article  CAS  PubMed  Google Scholar 

  17. Kim D, Weissman IL . Enrichment of xenotransplantable clonal cells in CD138high/CD138+ cells of multiple myeloma patients. AACR 101st Annual Meeting 2010: Abstract 4315, p. 1047.

  18. Yaccoby S, Epstein J . The proliferative potential of myeloma plasma cells manifest in the SCID-hu host. Blood 1999; 94: 3576–3582.

    CAS  PubMed  Google Scholar 

  19. Rasmussen T, Haaber J, Dahl IM, Knudsen LM, Kerndrup GB, Lodahl M et al. Identification of translocation products but not K-RAS mutations in memory B cells from patients with multiple myeloma. Haematologica 2010; 95: 1730–1737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank Dr Alberto Orfao (Salamanca) for his expert advice with the cell sorting protocols. This work was supported by the European Community's Sixth Framework Programme by a grant to the Myeloma Stem Cell Network (MSCNET) and by the Austrian Forum against Cancer. SSS is also funded by Leukaemia & Lymphoma Research, UK.

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Author notes

  1. S S Sahota and N Zojer: These authors contributed equally to this work.

Authors and Affiliations

  1. First Department of Medicine, Center for Oncology and Haematology, Wilhelminen Hospital, Vienna, Austria

    S Pfeifer, H Ludwig & N Zojer

  2. Department of Medicine, and Department of Hematology, Cytometry Service, Universidad de Salamanca, Hospital Universitario de Salamanca, Salamanca, Spain

    M Perez-Andres

  3. Cancer Sciences Division, Tumour Immunogenetics Group, School of Medicine, University of Southampton, Southampton, UK

    S S Sahota

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  1. S Pfeifer
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Correspondence to N Zojer.

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Pfeifer, S., Perez-Andres, M., Ludwig, H. et al. Evaluating the clonal hierarchy in light-chain multiple myeloma: implications against the myeloma stem cell hypothesis. Leukemia 25, 1213–1216 (2011). https://doi.org/10.1038/leu.2011.70

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