Global Gene Expression Profiling in the Study of Multiple Myeloma

Progress in Hematology

Abstract

Multiple myeloma (MM) is a rare but uniformly fatal malignancy of antibody-secreting plasma cells. Although several key molecular events in disease initiation or progression have been confirmed (eg,FGFR3/MMSET activation) or implicated (eg, chromosome 13 deletion), the mechanisms of MM development remain enigmatic. Although it is generally indistinguishable morphologically, MM importantly exhibits a tremendous degree of variability in its clinical course, with some patients surviving only months and others for many years. However, measures of current laboratory parameters can account for no more than 20% of this outcome variability. Furthermore, the means by which current drugs impart their anti-MM effect are mostly unknown.The development of serious comorbidities, such as osteopenia and/or focal lytic lesions of bone, is also poorly understood. Finally, very little knowledge exists concerning the molecular triggers for the conversion of benign monoclonal gammopathy of undetermined significance (MGUS) to overt MM. Given that abnormal gene expression lies at the heart of most if not all cancers, high-throughput global gene expression profiling has become a powerful tool for investigating the molecular biology and clinical behaviors. Here I discuss recent progress made in addressing many of these issues through the molecular dissection of the transcriptome of normal plasma cells, MGUS, and MM.

Key words

Microarray Gene expression profiling Multiple myeloma MGUS Bone disease Therapy 

References

  1. 1.
    Schena M, Shalon D, Davis RW, Brown PO. Quantitative monitoring of gene expression patterns with a complementary DNA microarray.Science. 1995;270:467–470.PubMedCrossRefGoogle Scholar
  2. 2.
    Schena M, Shalon D, Heller R, Chai A, Brown PO, Davis RW. Parallel human genome analysis: microarray-based expression monitoring of 1000 genes.Proc Natl Acad Sci USA. 1996;93:10614–10619.PubMedCrossRefGoogle Scholar
  3. 3.
    Fodor SP, Read JL, Pirrung MC, Stryer L, Lu AT, Solas D. Lightdirected, spatially addressable parallel chemical synthesis.Science. 1991;251:767–773.PubMedCrossRefGoogle Scholar
  4. 4.
    Lipshutz RJ, Fodor SP, Gingeras TR, Lockhart DJ. High density synthetic oligonucleotide arrays.Nat Genet. 1999; 21(suppl 1):20–24.PubMedCrossRefGoogle Scholar
  5. 5.
    DeRisi J, Penland L, Brown PO, et al. Use of a cDNA microarray to analyze gene expression patterns in human cancer.Nat Genet. 1996;14:457–460.PubMedCrossRefGoogle Scholar
  6. 6.
    Golub TR, Slonim DK, Tamayo P. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring.Science. 1999;286:531–537.PubMedCrossRefGoogle Scholar
  7. 7.
    Alizadeh AA, Eisen MB, Davis RE. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling.Nature. 2000;403:503–511.PubMedCrossRefGoogle Scholar
  8. 8.
    Singh D, Febbo P, Ross K, et al. Gene expression correlates of clinical prostate cancer.Cancer Cell. 2002;1:203–209.PubMedCrossRefGoogle Scholar
  9. 9.
    Zhan F, Hardin J, Kordsmeier B, et al. Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells.Blood. 2002;99:1745–1757.PubMedCrossRefGoogle Scholar
  10. 10.
    Shipp MA, Ross KN, Tamayo P, et al. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning.Nat Med. 2002;8:68–74.PubMedCrossRefGoogle Scholar
  11. 11.
    Yeoh EJ, Ross ME, Shurtleff SA, et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling.Cancer Cell. 2002;1:133–143.PubMedCrossRefGoogle Scholar
  12. 12.
    Ramaswamy S, Ross KN, Lander ES, Golub TR. A molecular signature of metastasis in primary solid tumors.Nat Genet. 2003;33:49–544.PubMedCrossRefGoogle Scholar
  13. 13.
    Barlogie B, Shaughnessy J, Munshi N, Epstein J. Plasma cell myeloma. In: Beutler E, Lichtman M, Coller B, Kipps T, eds. Williams Hematology. 6th ed. New York, NY: McGraw-Hill; 2001:1279–1304.Google Scholar
  14. 14.
    Munshi N, Tricot G, Barlogie B. Plasma cell neoplasms. In: DeVita VT, Hellman S, Rosenberg S, eds. Cancer Principles and Practice of Oncology. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:2465–2499.Google Scholar
  15. 15.
    Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance.N Engl J Med. 2002;346:564–569.PubMedCrossRefGoogle Scholar
  16. 16.
    Kuehl WM, Bergsagel PL. Multiple myeloma: evolving genetic events and host interactions.Nat Rev Cancer. 2002;2:175–187.PubMedCrossRefGoogle Scholar
  17. 17.
    De Vos J, Couderc G, Tarte K, et al. Identifying intercellular signaling genes expressed in malignant plasma cells by using complementary DNA arrays.Blood. 2001;98:771–780.CrossRefGoogle Scholar
  18. 18.
    Claudio JO, Masih-Khan E, Tang H, et al. A molecular compendium of genes expressed in multiple myeloma.Blood. 2002;100:2175–2186.PubMedCrossRefGoogle Scholar
  19. 19.
    Zhan F, Tian E, Bumm K, Smith R, Barlogie B, Shaughnessy J. Gene expression profiling of human plasma cell differentiation and classification of multiple myeloma based on similarities to distinct stages of late-stage B-cell development.Blood. 2003;101:1128–1140.PubMedCrossRefGoogle Scholar
  20. 20.
    Tarte K, De Vos J, Thykjaer T, et al. Generation of polyclonal plasmablasts from peripheral blood B cells: a normal counterpart of malignant plasmablasts.Blood. 2002;100:1113–1122.PubMedGoogle Scholar
  21. 21.
    van Steensel B, Smogorzewska A, de Lange T. TRF2 protects human telomeres from end-to-end fusions.Cell. 1998;92:401–413.PubMedCrossRefGoogle Scholar
  22. 22.
    Sze DM, Toellner KM, Garcia de Vinuesa C, Taylor DR, MacLennan IC. Intrinsic constraint on plasmablast growth and extrinsic limits of plasma cell survival.J Exp Med. 2000;192:813–821.PubMedCrossRefGoogle Scholar
  23. 23.
    Merville P, Dechanet J, Desmouliere A, et al. Bcl-2+ tonsillar plasma cells are rescued from apoptosis by bone marrow fibroblasts.J Exp Med. 1996;183:227–236.PubMedCrossRefGoogle Scholar
  24. 24.
    Garrett-Sinha LA, Dahl R, Rao S, Barton KP, Simon MC. PU.1 exhibits partial functional redundancy with Spi-B, but not with Ets-1 or Elf-1.Blood. 2001;97:2908–2912.PubMedCrossRefGoogle Scholar
  25. 25.
    Muthusamy N, Barton K, Leiden JM. Defective activation and survival of T cells lacking the Ets-1 transcription factor.Nature. 1995; 377:639–642.PubMedCrossRefGoogle Scholar
  26. 26.
    Bories JC, Willerford DM, Grevin D, et al. Increased T-cell apoptosis and terminal B-cell differentiation induced by inactivation of the Ets-1 proto-oncogene.Nature. 1995;377:635–638.PubMedCrossRefGoogle Scholar
  27. 27.
    Barton K, Muthusamy N, Fischer C, et al. The Ets-1 transcription factor is required for the development of natural killer cells in mice.Immunity. 1998;9:555–563.PubMedCrossRefGoogle Scholar
  28. 28.
    Eisenbeis CF, Singh H, Storb U. Pip, a novel IRF family member, is a lymphoid-specific, PU.1-dependent transcriptional activator.Genes Dev. 1995;9:1377–1387.PubMedCrossRefGoogle Scholar
  29. 29.
    Jacobs JJ, Scheijen B, Voncken JW, Kieboom K, Berns A, van Lohuizen M. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF.Genes Dev. 1999;13:2678–2690.PubMedCrossRefGoogle Scholar
  30. 30.
    van Lohuizen M, Verbeek S, Scheijen B, Wientjens E, van der Gulden H, Berns A. Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging.Cell. 1991;65:737–7522.PubMedCrossRefGoogle Scholar
  31. 31.
    Yu J, Angelin-Duclos C, Greenwood J, Liao J, Calame K. Transcriptional repression by blimp-1 (PRDI-BF1) involves recruitment of histone deacetylase.Mol Cell Biol. 2000;20:2592–2603.PubMedCrossRefGoogle Scholar
  32. 32.
    Medina F, Segundo C, Campos-Caro A, Gonzalez-Garcia I, Brieva JA. The heterogeneity shown by human plasma cells from tonsil, blood, and bone marrow reveals graded stages of increasing maturity, but local profiles of adhesion molecule expression.Blood. 2002;99:2154–2161.PubMedCrossRefGoogle Scholar
  33. 33.
    Shaughnessy J Jr, Gabrea A, Qi Y, et al. Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma.Blood. 2001;98:217–223.PubMedCrossRefGoogle Scholar
  34. 34.
    Zhan F, Walker R, Santra M, et al. Gene expression profiles can identify known and suspected multiple myeloma associated 14q32 translocations.Blood. 2002;100:1190a.Google Scholar
  35. 35.
    Santra M, Zhan F, Tian E, Barlogie B, Shaughnessy J. A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lack FGFR3 expression but maintain an IGH/MMSET fusion transcript. Blood. In press.Google Scholar
  36. 36.
    Avet-Loiseau H, Facon T, Grosbois B, et al. 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation.Blood. 2002;99:2185–2191.PubMedCrossRefGoogle Scholar
  37. 37.
    Shaughnessy J, Tian E, Sawyer J, et al. Prognostic impact of cytogenetic and interphase FISH defined chromosome 13 deletion in multiple myeloma: early results of total therapy II.Br J Haematol. 2003;120:44–52.PubMedCrossRefGoogle Scholar
  38. 38.
    Shaughnessy J, Barlogie B, Sawyer J, et al. Continuous absence of metaphase-defined abnormalities especially of chromosome 13 and hypodiploidy assures long-term survival in multiple myeloma treated with total therapy I: interpretation in the context of global gene expression. Blood. In press.Google Scholar
  39. 39.
    Shaughnessy J, Tian E, Sawyer J, et al. High incidence of chromosome 13 deletion in multiple myeloma detected by multiprobe interphase FISH.Blood. 2000;96:1505–1511.PubMedGoogle Scholar
  40. 40.
    Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response.Proc Natl Acad Sci U S A. 2001;98:5116–5121.PubMedCrossRefGoogle Scholar
  41. 41.
    Gruber SB, Ellis NA, Scott KK, et al. BLM heterozygosity and the risk of colorectal cancer.Science. 2002;297:2013.PubMedCrossRefGoogle Scholar
  42. 42.
    Goss KH, Risinger MA, Kordich JJ, et al. Enhanced tumor formation in mice heterozygous for Blm mutation.Science. 2002;297:2051–20533.PubMedCrossRefGoogle Scholar
  43. 43.
    Calin GA, Dumitru CD, Shimizu M, et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia.Proc Natl Acad Sci U S A. 2002; 99:15524–15529.PubMedCrossRefGoogle Scholar
  44. 44.
    Migliazza A, Bosch F, Komatsu H, et al. Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia.Blood. 2001;97:2098–2104.PubMedCrossRefGoogle Scholar
  45. 45.
    Georgii-Hemming P, Wiklund HJ, Ljunggren O, Nilsson K. Insulinlike growth factor I is a growth and survival factor in human multiple myeloma cell lines.Blood. 1996;88:2250–2258.PubMedGoogle Scholar
  46. 46.
    Ge N-L, Rudikoff S. Insulin-like growth factor I is a dual effector of multiple myeloma cell growth.Blood. 2000;96:2856–2861.PubMedGoogle Scholar
  47. 47.
    Qiang Y-W, Kopantzev E, Rudikoff S. Insulinlike growth factor-I signaling in multiple myeloma: downstream elements, functional correlates, and pathway cross-talk.Blood. 2002;99:4138–4146.PubMedCrossRefGoogle Scholar
  48. 48.
    Standal T, Borset M, Lenhoff S, et al. Serum insulinlike growth factor is not elevated in patients with multiple myeloma but is still a prognostic factor.Blood. 2002;100:3925–3929.PubMedCrossRefGoogle Scholar
  49. 49.
    Tibshirani R, Hastie T, Narasimhan B, Chu G. Diagnosis of multiple cancer types by shrunken centroids of gene expression.Proc Natl Acad Sci U S A. 2002;99:6567–6572.PubMedCrossRefGoogle Scholar
  50. 50.
    Townsley F, Aristarkhov A, Beck S, Hershko A, Ruderman J. Dominant-negative cyclin-selective ubiquitin carrier protein E2- C/UbcH10 blocks cells in metaphase.Proc Natl Acad Sci U S A. 1997;94:2362–2367.PubMedCrossRefGoogle Scholar
  51. 51.
    Lin H, Liu XY, Subramanian B, Nakeff A, Valeriote F, Chen BD. Mitotic arrest induced by XK469, a novel antitumor agent, is correlated with the inhibition of cyclin B1 ubiquitination.Int J Cancer. 2002;97:121–128.PubMedCrossRefGoogle Scholar
  52. 52.
    Shaughnessy J, Zhan F, McCastlain K, Tian E, Tricot G, Barlogie B. Gene expression profiling in the prediction of response of multiple myeloma to the proteasome inhibitor PS-341.Blood. 2002;100:1512a.Google Scholar
  53. 53.
    Shaughnessy J, Zhan F, Kordsmeier B, Randolph C, McCastlain K, Barlogie B. Gene expression profiling (GEP) after short term invivo treatment identifies potential mechanisms of action of current drugs used to treat multiple myeloma.Blood. 2002;100:781a.Google Scholar
  54. 54.
    Zhang B, Gojo I, Fenton RG. Myeloid cell factor-1 is a critical survival factor for multiple myeloma.Blood. 2002;99:1885–1893.PubMedCrossRefGoogle Scholar
  55. 55.
    Derenne S, Monia B, Dean NM, et al. Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(L) is an essential survival protein of human myeloma cells.Blood. 2002;100:194–199.PubMedCrossRefGoogle Scholar
  56. 56.
    Gupta D, Treon SP, Shima Y, et al. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications.Leukemia. 2001; 15:1950–1961.PubMedGoogle Scholar
  57. 57.
    Henning KA, Li L, Iyer N, et al. The Cockayne syndrome group A gene encodes a WD repeat protein that interacts with CSB protein and a subunit of RNA polymerase II TFIIH.Cell. 1995;82:555–564.PubMedCrossRefGoogle Scholar
  58. 58.
    Glinka A, Wu W, Delius H, Monaghan AP, Blumenstock C, Niehrs C. Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction.Nature. 1998;391:357–362.PubMedCrossRefGoogle Scholar
  59. 59.
    Bafico A, Liu G, Yaniv A, Gazit A, Aaronson SA. Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow.Nat Cell Biol. 2001;3:683–686.PubMedCrossRefGoogle Scholar
  60. 60.
    Semenov MV, Tamai K, Brott BK, Kuhl M, Sokol S, He X. Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6.Curr Biol. 2001;11:951–961.PubMedCrossRefGoogle Scholar
  61. 61.
    Mao B, Wu W, Li Y, et al. LDL-receptor-related protein 6 is a receptor for Dickkopf proteins.Nature. 2001;411:321–325.PubMedCrossRefGoogle Scholar
  62. 62.
    Fedi P, Bafico A, Nieto Soria A, et al. Isolation and biochemical characterization of the human Dkk-1 homologue, a novel inhibitor of mammalian Wnt signaling.J Biol Chem. 1999;274:19465–19472.PubMedCrossRefGoogle Scholar
  63. 63.
    Wang J, Shou J, Chen X. Dickkopf-1, an inhibitor of the Wnt signaling pathway, is induced by p53.Oncogene. 2000;19:1843–1848.PubMedCrossRefGoogle Scholar
  64. 64.
    Grotewold L, Ruther U. The Wnt antagonist Dickkopf-1 is regulated by Bmp signaling and c-Jun and modulates programmed cell death.EMBO J. 2002;21:966–975.PubMedCrossRefGoogle Scholar
  65. 65.
    Shou J, Ali-Osman F, Multani AS, Pathak S, Fedi P, Srivenugopal KS. Human Dkk-1, a gene encoding a Wnt antagonist, responds to DNA damage and its overexpression sensitizes brain tumor cells to apoptosis following alkylation damage of DNA.Oncogene. 2002;21:878–8899.PubMedCrossRefGoogle Scholar
  66. 66.
    Hjertner O, Hjorth-Hansen H, Borset M, Seidel C, Waage A, Sundan A. Bone morphogenetic protein-4 inhibits proliferation and induces apoptosis of multiple myeloma cells.Blood. 2001;97:516–522.PubMedCrossRefGoogle Scholar
  67. 67.
    Mukhopadhyay M, Shtrom S, Rodriguez-Esteban C, et al. Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse.Dev Cell. 2001;1:423–434.PubMedCrossRefGoogle Scholar
  68. 68.
    Zhan F, Randolph C, Suva L, Barlogie B, Epstein J, Shaughnessy J. Gene expression profiling of multiple myeloma plasma cells allows identification of potential molecular determinants of lytic bone disease.Blood. 2002;100:782a.Google Scholar
  69. 69.
    Leyns L, Bouwmeester T, Kim SH, Piccolo S, De Robertis EM. Frzb-1 is a secreted antagonist of Wnt signaling expressed in the Spemann organizer.Cell. 1997;88:747–756.PubMedCrossRefGoogle Scholar
  70. 70.
    Gong Y, Slee RB, Fukai N, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.Cell. 2001;107:513–5233.PubMedCrossRefGoogle Scholar
  71. 71.
    Little RD, Carulli JP, Del Mastro RG, et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait.Am J Hum Genet. 2002;70:11–19.PubMedCrossRefGoogle Scholar
  72. 72.
    Boyden LM, Mao J, Belsky J, et al. High bone density due to a mutation in LDL-receptor-related protein 5.N Engl J Med. 2002; 346:1513–1521.PubMedCrossRefGoogle Scholar
  73. 73.
    Kato M, Patel MS, Levasseur R, et al. Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor.J Cell Biol. 2002;157:303–314.PubMedCrossRefGoogle Scholar
  74. 74.
    Sausville EA, Feigal E. Evolving approaches to cancer drug discovery and development at the National Cancer Institute, USA.Ann Oncol. 1999;10:1287–1291.PubMedCrossRefGoogle Scholar
  75. 75.
    Monga M, Sausville EA. Developmental therapeutics program at the NCI: molecular target and drug discovery process.Leukemia 2002;16:520–526.PubMedCrossRefGoogle Scholar
  76. 76.
    Scherf U, Ross DT, Waltham M, et al. A gene expression database for the molecular pharmacology of cancer.Nat Genet. 2001;24:236–244.CrossRefGoogle Scholar
  77. 77.
    Zaharevitz DW, Holbeck SL, Bowerman C, Svetlik PA. COMPARE: a web accessible tool for investigating mechanisms of cell growth inhibition.J Mol Graph Model. 2002;20:297–303.PubMedCrossRefGoogle Scholar
  78. 78.
    Parr AL, Myers TG, Holbeck SL, Loh YJ, Allegra CJ. Thymidylate synthase as a molecular target for drug discovery using the National Cancer Institute’s Anticancer Drug Screen.Anticancer Drugs. 2001;12:569–574.PubMedCrossRefGoogle Scholar
  79. 79.
    Beaupre D, Grad J, Bahlis N, Boise L, Lichtenheld M. Preclinical investigation of farnesyltransferase inhibitor for myeloma.Blood. 2002;98:640a.Google Scholar
  80. 80.
    Goffin J, Eisenhauer E. DNA methyltransferase inhibitors: state of the art.Ann Oncol. 2002;13:1699–1671.PubMedCrossRefGoogle Scholar
  81. 81.
    Hanahan D, Weinberg RA. The hallmarks of cancer.Cell. 2000;100:57–700.PubMedCrossRefGoogle Scholar
  82. 82.
    Hideshima T, Chauhan D, Podar K, Schlossman RL, Richardson P, Anderson KC. Novel therapies targeting the multiple myeloma cell and its bone marrow microenvironment.Semin Oncol. 2001;28:607–6122.PubMedCrossRefGoogle Scholar
  83. 83.
    Hideshima T, Anderson KC. Molecular mechanisms of novel therapeutic approaches for multiple myeloma.Nat Rev Cancer. 2002;2:927–9377.PubMedCrossRefGoogle Scholar
  84. 84.
    Yaccoby S, Pearse RN, Johnson CL, Barlogie B, Choi Y, Epstein J. MM interacts with the bone marrow microenvironment to induce osteoclastogenesis and is dependent on osteoclast activity.Br J Haematol. 2002;116:278–290.PubMedCrossRefGoogle Scholar
  85. 85.
    Shaughnessy J, Fenghuang Z, Kordsmeier B, Tian E, Smith R, Barlogie B. Gene expression profiling of the bone marrow microenvironment in patients with multiple myeloma, monoclonal gammopathy of undetermined significance and normal healthy donors.Blood. 2002;100:382a.Google Scholar
  86. 86.
    Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS. Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines.Blood. 1999;93:1658–1667.PubMedGoogle Scholar
  87. 87.
    Hazlehurst LA, Damiano JS, Buyuksal I, Pledger WJ, Dalton WS. Adhesion to fibronectin via beta1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR).Oncogene. 2000;19:4319–4327.PubMedCrossRefGoogle Scholar
  88. 88.
    Shain KH, Landowski TH, Dalton WS. The tumor microenvironment as a determinant of cancer cell survival: a possible mechanism for de novo drug resistance.Curr Opin Oncol. 2000;12:557–563.PubMedCrossRefGoogle Scholar
  89. 89.
    Barille S, Akhoundi C, Collette M, et al. Metalloproteinases in multiple myeloma: production of matrix metalloproteinase-9 (MMP-9), activation of proMMP-2, and induction of MMP-1 by multiple myeloma cells.Blood. 1997;90:1649–1655.PubMedGoogle Scholar
  90. 90.
    Barille S, Collette M, Thabard W, Bleunven C, Bataille R, Amiot M. Soluble IL-6R alpha upregulated IL-6, MMP-1 and MMP-2 secretion in bone marrow stromal cells.Cytokine. 2000;12:1426–1429.PubMedCrossRefGoogle Scholar
  91. 91.
    Vacca A, Ribatti D, Presta M, et al. Bone marrow neovascularization, PC angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma.Blood. 1999;93:3064–3073.PubMedGoogle Scholar
  92. 92.
    Kelly T, Borset M, Abe E, Gaddy-Kurten D, Sanderson RD. Matrix metalloproteinases in multiple myeloma.Leuk Lymphoma. 2000; 37:273–281.PubMedGoogle Scholar
  93. 93.
    Wahlgren J, Maisi P, Sorsa T, et al. Expression and induction of collagenases (MMP-8 and -13) in plasma cells associated with bonedestructive lesions.J Pathol. 2001;194:217–224.PubMedCrossRefGoogle Scholar
  94. 94.
    Hardin J, Waddell M, Cheng J, et al. Toward the development of diagnostic models capable of distinguishing multiple myeloma, monoclonal gammopathy of undetermined significance, and normal plasma cells using global gene expression profiles.Blood. 2002;100:378a.Google Scholar

Copyright information

© The Japanese Society of Hematology 2003

Authors and Affiliations

  1. 1.Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics, Myeloma Institute for Research and TherapyUniversity of Arkansas for Medical SciencesLittle RockUSA

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