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.
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Schena M, Shalon D, Davis RW, Brown PO. Quantitative monitoring of gene expression patterns with a complementary DNA microarray.Science. 1995;270:467–470.
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.
Fodor SP, Read JL, Pirrung MC, Stryer L, Lu AT, Solas D. Lightdirected, spatially addressable parallel chemical synthesis.Science. 1991;251:767–773.
Lipshutz RJ, Fodor SP, Gingeras TR, Lockhart DJ. High density synthetic oligonucleotide arrays.Nat Genet. 1999; 21(suppl 1):20–24.
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.
Golub TR, Slonim DK, Tamayo P. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring.Science. 1999;286:531–537.
Alizadeh AA, Eisen MB, Davis RE. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling.Nature. 2000;403:503–511.
Singh D, Febbo P, Ross K, et al. Gene expression correlates of clinical prostate cancer.Cancer Cell. 2002;1:203–209.
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.
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.
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.
Ramaswamy S, Ross KN, Lander ES, Golub TR. A molecular signature of metastasis in primary solid tumors.Nat Genet. 2003;33:49–544.
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.
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.
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.
Kuehl WM, Bergsagel PL. Multiple myeloma: evolving genetic events and host interactions.Nat Rev Cancer. 2002;2:175–187.
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.
Claudio JO, Masih-Khan E, Tang H, et al. A molecular compendium of genes expressed in multiple myeloma.Blood. 2002;100:2175–2186.
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.
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.
van Steensel B, Smogorzewska A, de Lange T. TRF2 protects human telomeres from end-to-end fusions.Cell. 1998;92:401–413.
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.
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.
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.
Muthusamy N, Barton K, Leiden JM. Defective activation and survival of T cells lacking the Ets-1 transcription factor.Nature. 1995; 377:639–642.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Gruber SB, Ellis NA, Scott KK, et al. BLM heterozygosity and the risk of colorectal cancer.Science. 2002;297:2013.
Goss KH, Risinger MA, Kordich JJ, et al. Enhanced tumor formation in mice heterozygous for Blm mutation.Science. 2002;297:2051–20533.
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.
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.
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.
Ge N-L, Rudikoff S. Insulin-like growth factor I is a dual effector of multiple myeloma cell growth.Blood. 2000;96:2856–2861.
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.
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.
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.
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.
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.
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.
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.
Zhang B, Gojo I, Fenton RG. Myeloid cell factor-1 is a critical survival factor for multiple myeloma.Blood. 2002;99:1885–1893.
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.
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.
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.
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.
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.
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.
Mao B, Wu W, Li Y, et al. LDL-receptor-related protein 6 is a receptor for Dickkopf proteins.Nature. 2001;411:321–325.
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.
Wang J, Shou J, Chen X. Dickkopf-1, an inhibitor of the Wnt signaling pathway, is induced by p53.Oncogene. 2000;19:1843–1848.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Sausville EA, Feigal E. Evolving approaches to cancer drug discovery and development at the National Cancer Institute, USA.Ann Oncol. 1999;10:1287–1291.
Monga M, Sausville EA. Developmental therapeutics program at the NCI: molecular target and drug discovery process.Leukemia 2002;16:520–526.
Scherf U, Ross DT, Waltham M, et al. A gene expression database for the molecular pharmacology of cancer.Nat Genet. 2001;24:236–244.
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.
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.
Beaupre D, Grad J, Bahlis N, Boise L, Lichtenheld M. Preclinical investigation of farnesyltransferase inhibitor for myeloma.Blood. 2002;98:640a.
Goffin J, Eisenhauer E. DNA methyltransferase inhibitors: state of the art.Ann Oncol. 2002;13:1699–1671.
Hanahan D, Weinberg RA. The hallmarks of cancer.Cell. 2000;100:57–700.
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.
Hideshima T, Anderson KC. Molecular mechanisms of novel therapeutic approaches for multiple myeloma.Nat Rev Cancer. 2002;2:927–9377.
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.
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.
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.
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.
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.
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.
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.
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.
Kelly T, Borset M, Abe E, Gaddy-Kurten D, Sanderson RD. Matrix metalloproteinases in multiple myeloma.Leuk Lymphoma. 2000; 37:273–281.
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.
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.
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Shaughnessy, J.D. Global Gene Expression Profiling in the Study of Multiple Myeloma. Int J Hematol 77, 213–225 (2003). https://doi.org/10.1007/BF02983777
- Gene expression profiling
- Multiple myeloma
- Bone disease