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Blood, Vol. 91 No. 1 (January 1), 1998:
pp. 3-21
REVIEW ARTICLE
By
From Medizinische Klinik, Klinikum Innenstadt, and Genzentrum,
Universität München, München, Germany; Cornell
University Medical College, New York, NY; and Dana-Farber Cancer
Institute and Harvard Medical School, Boston, MA.
MULTIPLE MYELOMA (MM) is a clonal B-cell
neoplasm that affects terminally differentiated B cells (ie, plasma
cells) and may proceed through different phases: an inactive phase in
which tumor cells are nonproliferating mature plasma cells, an active
phase with a small percentage (<1%) of proliferating plasmablastic
cells, and a fulminant phase with the frequent occurrence of
extramedullary proliferation and an increase in plasmablastic cells.
During the past years, considerable progress has been made in
identifying some of the critical components of neoplastic
transformation in MM. This review intends to propose a model of a
stepwise malignant transformation during MM pathogenesis. Both
diagnostic and therapeutic implications of this model will be
discussed.
Normal Plasma Cell Development
The Malignant Myeloma Cell Corresponds to a Long-lived Plasma Cell
Karyotypic Abnormalities
Low Incidence of Karyotypically Detectable Translocations to Ig Loci in MM The hallmark genetic lesion in many B-lymphocyte tumors involves dysregulation of an oncogene as a consequence of a translocation involving the IgH locus (14q32.3), or, less frequently, variant translocations involving one of the IgL loci (2p12, or 22q11,
 ).19-23 From conventional karyotypic analyses,
translocations involving 14q32 appear to occur in about 20% to 40% of
myeloma tumors with an abnormal karyotype (references as above). The
incidence of these translocations is significantly higher at the
extramedullary phase of the disease and in cell lines, perhaps due to a
higher number of metaphase spreads that can be examined. In about 30%
of these translocations, the partner chromosomal locus is 11q13 (bcl-1,
cyclin D1) but in most cases the partner is not identified (14q32+).
Other recurrent partner loci have been identified infrequently, eg,
8q24(c-myc) in less than 5%, 18q21(bcl-2), 11q23(MLL-1), 6p21.1.
Variant translocations involving 8q24(c-myc) have been detected in
a few percent of myeloma tumors.6,9,11,13,14
Translocations Involving the IgH Locus Are Essentially Invariant in Myeloma Cell Lines Recently, by combining conventional karyotypic analysis with a comprehensive Southern blot assay that detects translocations involving IgH switch regions, it has become apparent that most (19 of 21) myeloma cell lines and the one primary tumor fully examined have IgH translocations that mainly involve IgH switch regions.24-26 Notably, seven of nine cell lines with no karyotypically detectable 14q32 translocation have a translocation involving an IgH switch region using this assay. For four of the cell lines it was possible to examine primary tumor material and show the presence of the translocation breakpoint, indicating that the translocations are not an artifact of cell culture. In six cases, there is translocation involving 11q13 and overexpression of cyclin D1. The four cloned translocation breakpoints are into or near an IgH switch region, whereas the same translocation in mantle cell lymphoma invariably involves JH regions.19 Five additional lines and the tumor have been determined to have an IgH switch translocation breakpoint involving the telomeric end of chromosome 4 (ie, 4p16.3, near the tip of 4p), despite the fact that no karyotypic translocation was detected in 5 of 6 of these samples.27 The apparent oncogene dysregulated by the 4;14 translocation is the fibroblast growth factor receptor 3 (FGFR3) gene. The cloning of three other translocation breakpoints identified four different chromosome loci (6, 8q24, 16q23, and 21q22).24IgH Translocations Involving a Promiscuous Array of Partner Chromosomes: Possibly a Universal and Early Event in MM Based on the results presented above, it appears that translocations to the IgH or one of the IgL loci may be a nearly universal event in MM despite the apparent low incidence by karyotypic analysis. These translocations are usually into IgH switch regions. They involve two nonrandom loci, ie, 11q13 (bcl-1, cyclin D1) in 25% and 4p16.3 (FGFR3) in 25%. The remaining 50% or so of cases involve a promiscuous array of chromosome partners, some of which have been identified in at least two unrelated tumors [8q24(c-myc), 18q21(bcl-2), 6p21.1 (?), 11q23 (MLL-1)], and others of which have been identified in only one tumor thus far [1p13, 1q21, 3p11, 6p25, 7q11, 12q24, 16q23, and 21q22]. Considering the developmental pathway for long-lived plasma cells (Fig 1), the timing of normal IgH switching, and the shared productive switch for paired MGUS and myeloma cells, we hypothesize that this translocation affects the nonproductive Ig allele, and may be one of the earliest molecular events in the pathogenesis of MM, although this remains to be confirmed.Oncogenes Dysregulated by Recurrent IgH Translocations in Myeloma c-myc. c-myc, the cellular homologue of the transforming gene v-myc from the oncogenic avian retrovirus, appears to play a central role in controlling proliferation, differentiation, and apoptosis.31-33 In BALB/c plasmacytomas and rat immunocytomas, activation of c-myc by chromosome translocation into a switch region of the IgH locus (or by a variant translocation to one of the IgL loci) is a universal event.22,34,35 In human MM, by contrast, a t(8;14) occurs in less then 5% of cases, and variant translocations involving 8q24 are reported in only a few percent of tumors (references above). Karyotypic abnormalities of 8q24 other than translocation to one of the Ig loci have also been identified in a small fraction of myeloma samples.9 DNA rearrangement of c-myc has been detected by Southern blot in a few patients.3,36-38 Rearrangements have also been seen in the MLVI-4 locus located 20 kb downstream of c-myc.38,39 Infrequently, DNA amplification of c-myc has also been reported.3,36
bcl-1/PRAD-1/cyclin D1.
The bcl-1 locus at 11q13 is involved in recurrent translocations to
14q32 in chronic lymphocytic leukemia (CLL), lymphomas,
and myeloma. This translocation is almost invariant in mantle cell
lymphoma, where the breakpoints on 11q13 are clustered predominantly in
one region (called MTC, for major translocation cluster), and the
breakpoints in the IgH locus are in the JH regions. Rearrangements
involving the MTC are rare in myeloma [0 of 58 unselected; and 0 of 13
with t(11;14)].19,39,47-51 The first t(11;14) breakpoints
have recently been cloned from myeloma samples and in contrast to
mantle zone lymphoma, the MTC region was not involved, and the
breakpoints in the IgH locus are frequently into switch
regions.24,26 The cyclin D1 gene is approximately 120 kb
telomeric to these breakpoints. Cyclin D1 together with CDK4
phosphorylates (and inactivates) pRB and allows for progression through
the G1 phase of the cell cycle.52 Unlike other genes
identified in this region of 11q13, there is a close association
between t(11;14) and enhanced expression of cyclin D1.53
Furthermore, a variant translocation (ie, involving a light chain gene)
just telomeric to cyclin D154 and a translocation
breakpoint within the 3 FGFR3. Recently the fibroblast growth factor receptor 3 gene at 4p16.3 was identified as dysregulated by t(4;14)(p16;q32) in 5 of 21 myeloma cell lines and 3 of 11 primary tumors.27 This novel, karyotypically silent translocation has not been described before and may be unique to myeloma, although it has not yet been examined in other tumors, nor has it been extensively studied in primary tumor samples. Because it involves the telomere of 4p16 this translocation generally is not identified by conventional karyotypes, and more sensitive techniques (eg, fluorescent in situ hybridization or Southern blot) are required to detect it. FGFR3 is normally expressed in the lung, kidney, and the chondrocytes at the ends of growing bones. Different germline mutations of FGFR3 result in distinct dwarfing conditions of increasing severity: hypochondroplasia, achondroplasia, and thanatophoric dysplasia.58-63 FGFR3 is expressed at a high level only in those myeloma cell lines with t(4;14). Activating mutations of FGFR3 occur frequently in myeloma cell lines and primary tumors with 4;14 translocations (in 3 of 6 cell lines and 1 of 3 primary tumor samples). The same mutations have been described previously in patients with the most severe form of dwarfism, thanatophoric dysplasia, and they are thought (for some mutations proven) to be activating mutations.64,65 In addition, although both alleles are present in the genomic DNA, in each case only the mutant allele is expressed, indicating that the translocation has caused cis-dysregulation, ie, selective expression of this allele.
The Role of Growth Factors and the Bone Marrow (BM) Microenvironment The proliferation, differentiation, and function of lympho-hematopoietic cells is regulated by a complex network of lympho-hematopoietic growth factors and cell surface molecules which establish a fine-tuned communication between stroma cells and lympho-hematopoietic precursors in the BM.66-68 These growth factors bind to specific cell-surface receptors that belong to different families, the receptor tyrosine kinases and the hematopoietic cytokine receptors.69-72 The nature of the biological response to any growth factor is defined by the tissue or lineage distribution of growth factor receptors and by distinct transmembrane signaling events in which tyrosine kinases play a pivotal role.73,74
Additional Growth Factors for MM Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor with structural homology to IL-6.113,114 Moreover, the G-CSF receptor shares also some homology with gp130.115 Both G-CSF and IL-6 induce activation of NF-IL-6, a transcription factor involved in the synthesis of IL-6.116 G-CSF is a potent growth factor for freshly explanted myeloma cells, and MM cell lines may respond to G-CSF.76 The mechanism of action by which G-CSF mediates MM growth is unknown. However, the data caution that treatment of MM patients with G-CSF after high-dose chemotherapy or for stem cell harvest might eventually enhance proliferation of the tumor,76 although this has never been shown in clinical practice.
Factors Inhibiting the Growth of MM Cells Interferon- (IFN-) was reported to inhibit IL-6-dependent
proliferation of fresh MM cells.139 It did not affect the
endogenous IL-6 production, but seemed to act directly on MM cells. It
is possible that IFN- interferes with IL-6 transmembrane signaling,
resulting in enhanced apoptosis. Interestingly, IFN- also inhibits
cytokine-mediated bone resorption, which is a relevant clinical problem
in MM.76 TNF- and transforming growth factor-
(TFG-) are other potential inhibitors of the proliferative effects
of IL-6.140
Adhesion Molecules and Other Cell-Surface Antigens The differentiation of lymphoid precursor cells into mature B lymphocytes is accompanied by characteristic changes of cell-surface antigens. The application of high resolution, multiparameter flow cytometry has been used to identify and characterize normal plasma cells in the human BM. Plasma cells exist in at least two different subpopulations, early lymphoplasmacytoid plasma cells and late mature plasma cells.152 These two populations appeared phenotypically different, but both strongly express CD38. In distinction to mature plasma cells, early lymphoplasmacytoid cells express CD22, CD35, and surface IgE receptors, and intracytoplasmatic Ig light chain only at low density. Subpopulations of mature, normal plasma cells show a very heterogeneous immunophenotype in that they can express early B-cell antigens (CD19, CD20, CD10), myeloid antigens (CD13, CD33), HLA-DR, common hematopoietic antigens (CD45), and adhesion molecules (CD11b, CD11c).153
Mechanisms of Signal Transduction IL-6 receptor.
Because IL-6 is of central importance in the pathogenesis of MM, the
intracellular signaling events elicited by this cytokine are also of
potential relevance. Recently, some progress has been made in
understanding the biochemical events involved in IL-6 transmembrane
signaling at a molecular level (Fig 2).Binding of IL-6 to IL-6R
JAK-STAT pathway.
As indicated above, IL-6 binding to IL-6R Ras-MAP kinase signaling pathway. The three proteins encoded by the human ras genes (H-ras, K-ras, N-ras) are membrane-associated guanosine triphosphatases (GTPases) with a m.w. of 21 kD.199 These three proteins are usually referred to as Ras or p21ras. The essential feature of Ras is its ability to bind the guanine nucleotides GTP and guanosine diphosphate (GDP). Ras is active in the GTP-bound form, and inactive in the GDP-bound form. Ras functions as an important mediator of many biological responses stimulated by tyrosine kinases. Activation of Ras lies downstream of receptor and nonreceptor tyrosine kinases and upstream of a kinase cascade which includes other important signaling intermediates such as Raf-1 and MAPK (see below and Fig 2).200
Chromosomal aberrations increase with disease progression in MM,242 indicating that the transformation from MGUS to MM or plasma cell leukemia requires additional mutations to enable the malignant cell clone to survive and proliferate in the absence of the marrow microenvironment. Ras Mutations The above-described studies on IL-6 signaling strongly suggest a critical role for p21ras in the pathogenesis of MM. This hypothesis is further nourished by the finding that ras mutations occur in about 39% of newly diagnosed MM patients (Table 1). Interestingly, the frequency of ras mutations increases with disease progression: Mutations of N- and K-ras are rarely detected in solitary plasmacytoma and monoclonal gammopathies of undetermined significance (MGUS), but more frequently in MM (in 9% to 30%), and in the majority of terminal disease or plasma cell leukemia patients (63.6% to 70%).243-246 N-ras codon 61 mutations seem more frequent than N-ras codon 12 and 13, or K-ras mutations (Table 1).243-245
Inhibitors of Programmed Cell Death: p53 and bcl-2 Bcl-2 and related proteins. Apoptosis or programmed cell death is a process of pivotal importance during normal development, for immunoselection against autoreactive T and B cells, or in the elimination of old or damaged cells. Apoptosis is also induced by a variety of drugs, heat shock, or by growth factor deprivation. The membrane protein Bcl-2 is a highly conserved, ubiquitous membrane protein associated with the outer-membrane of mitochondria and nuclei, and with the endoplasmatic reticulum which regulates apoptosis.253 Overexpression of bcl-2 in cancer cells can result in chemoresistance and blocks apoptosis. Recent work has shown the existence of several Bcl-2-related proteins that can inhibit (Bcl-XL, Mcl-1, NR-13, A1, Bcl-W) or enhance (Bax, Bcl-XS, Bak, Bad) apoptosis.254,255 Bcl-2 forms inactivating or activating heterodimers with other proteins encoded by these genes of the bcl-2 superfamily. p53. The tumor suppressor gene p53 has many effects on cell growth and differentiation and is often viewed as a gate-keeper to enter the cell cycle. Recently, is has been found that p53 binds to response elements on bcl-2 and bax genes, resulting in the downregulation of bcl-2 and in an upregulation of bax. Therefore, it was postulated that p53 induces the synthesis of bax and reduces the synthesis of bcl-2, thereby affecting the balance between cell growth and death.264 Retinoblastoma (Rb) Gene and Other Cell-Cycle Regulatory Genes Rb.
The retinoblastoma tumor suppressor gene product (pRb) is involved in
cell growth and differentiation. pRb is a nuclear phosphoprotein that
suppresses the G1
Inhibitors of cyclin-dependent kinases.
The p16INK4A (p16) protein is an inhibitor of
cyclin-dependent kinases (CDK) 4 and CDK6. It is expressed in some MM
cells or cell lines, and a higher expression correlates with IL-6
responsiveness of more mature MM tumors (VLA-5+,
MPC+).284,285 In contrast, expression of cyclin D1 is more
frequent in immature MM tumors (VLA-5 p21WAF1.
p21WAF1 (p21) inhibits cell proliferation by both
p53-dependent and -independent mechanisms. It is believed that p21
protects from (p53 dependent) apoptosis by induction of cell-cycle
arrest and subsequent DNA repair.289,290 In the majority of
MM cells, p21 seems to be constitutively expressed, while it is not
detected in normal B cells.291 IL-6 downregulates and
IFN- MDM2.
The murine double minute 2 (MDM2) gene product facilitates the G1 Multiple Drug Resistance (MDR) Gene The MDR gene encodes a 170-kD p-glycoprotein which is responsible for the resistance of tumor cells to a variety of antineoplastic drugs. The amplification of MDR gene expression can be detected in myeloma cells, and its expression is correlated with a resistance to doxorubicin and vincristine (VAD regimen).293-295 Recently, clinical trials have been activated to overcome this treatment refractoriness with drug-resistance modifiers like cyclosporin A and verapamil.295
The central role of IL-6 as a growth factor for MM cells suggests that
strategies to block its effects could be exploited therapeutically.
This effect may be achieved either by conventional therapeutic agents
or by compounds specifically designed to block the action of IL-6.
Among the conventional agents is IFN-
Based on the information described above, we propose a working multi-step model of the molecular pathogenesis of myeloma (Fig 3). The cell that gives rise to myeloma appears to have passed through the pathway that generates the long-lived plasma cell which has a phenotype similar to myeloma cells. Thus, the oncogenic events in myeloma either occur after or do not interfere with the normal maturation process that generates long-lived plasma cells. Like a long-lived plasma cell, a myeloma cell has undergone three developmentally regulated changes in the DNA structure of the IgH and IgL loci, including productive V(D)J recombination of its IgH and IgL genes, somatic hypermutation of the IgH and IgL V regions, and productive IgH switch recombination to another IgH isotype. It is attractive to speculate that errors in one or more of these processes has caused genetic changes that contribute to the malignant process.
Submitted May 5, 1997;
accepted September 11, 1997.
P.L.B. would like to acknowledge the equal contribution of Michael Kuehl to our shared results and ideas presented here.
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O. Galm, H. Yoshikawa, M. Esteller, R. Osieka, and J. G. Herman SOCS-1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma Blood, April 1, 2003; 101(7): 2784 - 2788. [Abstract] [Full Text] [PDF]
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J. J. Keats, T. Reiman, C. A. Maxwell, B. J. Taylor, L. M. Larratt, M. J. Mant, A. R. Belch, and L. M. Pilarski In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression Blood, February 15, 2003; 101(4): 1520 - 1529. [Abstract] [Full Text] [PDF]
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A. C. Bharti, N. Donato, S. Singh, and B. B. Aggarwal Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and Ikappa Balpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis Blood, February 1, 2003; 101(3): 1053 - 1062. [Abstract] [Full Text] [PDF]
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 S. Barille-Nion, B. Barlogie, R. Bataille, P. L. Bergsagel, J. Epstein, R. G. Fenton, J. Jacobson, W. M. Kuehl, J. Shaughnessy, and G. Tricot Advances in Biology and Therapy of Multiple Myeloma Hematology, January 1, 2003; 2003(1): 248 - 278. [Abstract] [Full Text] [PDF]
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S. Yaccoby, C. L. Johnson, S. C. Mahaffey, M. J. Wezeman, B. Barlogie, and J. Epstein Antimyeloma efficacy of thalidomide in the SCID-hu model Blood, December 1, 2002; 100(12): 4162 - 4168. [Abstract] [Full Text] [PDF]
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I. Gojo, B. Zhang, and R. G. Fenton The Cyclin-dependent Kinase Inhibitor Flavopiridol Induces Apoptosis in Multiple Myeloma Cells through Transcriptional Repression and Down-Regulation of Mcl-1 Clin. Cancer Res., November 1, 2002; 8(11): 3527 - 3538. [Abstract] [Full Text] [PDF]
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C. Nabhan, D. Gajria, N. L. Krett, V. Gandhi, K. Ghias, and S. T. Rosen Caspase Activation Is Required for Gemcitabine Activity in Multiple Myeloma Cell Lines Mol. Cancer Ther., November 1, 2002; 1(13): 1221 - 1227. [Abstract] [Full Text] [PDF]
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M. Chatterjee, D. Honemann, S. Lentzsch, K. Bommert, C. Sers, P. Herrmann, S. Mathas, B. Dorken, and R. C. Bargou In the presence of bone marrow stromal cells human multiple myeloma cells become independent of the IL-6/gp130/STAT3 pathway Blood, October 16, 2002; 100(9): 3311 - 3318. [Abstract] [Full Text] [PDF]
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 G Pratt Molecular aspects of multiple myeloma Mol. Pathol., October 1, 2002; 55(5): 273 - 283. [Abstract] [Full Text] [PDF]
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E. Zenger, N. W. Abbey, M. D. Weinstein, L. Kapp, J. Reis, I. Gofman, C. Millward, R. Gascon, A. Elbaggari, B. G. Herndier, et al. Injection of Human Primary Effusion Lymphoma Cells or Associated Macrophages into Severe Combined Immunodeficient Mice Causes Murine Lymphomas Cancer Res., October 1, 2002; 62(19): 5536 - 5542. [Abstract] [Full Text] [PDF]
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 R. S. Abraham, M. C. Charlesworth, B. A.L. Owen, L. M. Benson, J. A. Katzmann, C. B. Reeder, and R. A. Kyle Trimolecular Complexes of {lambda} Light Chain Dimers in Serum of a Patient with Multiple Myeloma Clin. Chem., October 1, 2002; 48(10): 1805 - 1811. [Abstract] [Full Text] [PDF]
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R. F. J. Schop, W. M. Kuehl, S. A. Van Wier, G. J. Ahmann, T. Price-Troska, R. J. Bailey, S. M. Jalal, Y. Qi, R. A. Kyle, P. R. Greipp, et al. Waldenstrom macroglobulinemia neoplastic cells lack immunoglobulin heavy chain locus translocations but have frequent 6q deletions Blood, September 26, 2002; 100(8): 2996 - 3001. [Abstract] [Full Text] [PDF]
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L. Burdelya, R. Catlett-Falcone, A. Levitzki, F. Cheng, L. B. Mora, E. Sotomayor, D. Coppola, J. Sun, S. Sebti, W. S. Dalton, et al. Combination Therapy with AG-490 and Interleukin 12 Achieves Greater Antitumor Effects than Either Agent Alone Mol. Cancer Ther., September 1, 2002; 1(11): 893 - 899. [Abstract] [Full Text] [PDF]
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T. Hayashi, T. Hideshima, M. Akiyama, P. Richardson, R. L. Schlossman, D. Chauhan, N. C. Munshi, S. Waxman, and K. C. Anderson Arsenic Trioxide Inhibits Growth of Human Multiple Myeloma Cells in the Bone Marrow Microenvironment Mol. Cancer Ther., August 1, 2002; 1(10): 851 - 860. [Abstract] [Full Text] [PDF]
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R. Fonseca, R. J. Bailey, G. J. Ahmann, S. V. Rajkumar, J. D. Hoyer, J. A. Lust, R. A. Kyle, M. A. Gertz, P. R. Greipp, and G. W. Dewald Genomic abnormalities in monoclonal gammopathy of undetermined significance Blood, July 30, 2002; 100(4): 1417 - 1424. [Abstract] [Full Text] [PDF]
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M. Akiyama, T. Hideshima, T. Hayashi, Y.-T. Tai, C. S. Mitsiades, N. Mitsiades, D. Chauhan, P. Richardson, N. C. Munshi, and K. C. Anderson Cytokines Modulate Telomerase Activity in a Human Multiple Myeloma Cell Line Cancer Res., July 1, 2002; 62(13): 3876 - 3882. [Abstract] [Full Text] [PDF]
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 J L Xu, R Lai, T Kinoshita, N Nakashima, and T Nagasaka Proliferation, apoptosis, and intratumoral vascularity in multiple myeloma: correlation with the clinical stage and cytological grade J. Clin. Pathol., July 1, 2002; 55(7): 530 - 534. [Abstract] [Full Text] [PDF]
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R. Fonseca, E. A. Blood, M. M. Oken, R. A. Kyle, G. W. Dewald, R. J. Bailey, S. A. Van Wier, K. J. Henderson, J. D. Hoyer, D. Harrington, et al. Myeloma and the t(11;14)(q13;q32); evidence for a biologically defined unique subset of patients Blood, May 15, 2002; 99(10): 3735 - 3741. [Abstract] [Full Text] [PDF]
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N. Mitsiades, C. S. Mitsiades, V. Poulaki, D. Chauhan, P. G. Richardson, T. Hideshima, N. Munshi, S. P. Treon, and K. C. Anderson Biologic sequelae of nuclear factor-kappa B blockade in multiple myeloma: therapeutic applications Blood, May 13, 2002; 99(11): 4079 - 4086. [Abstract] [Full Text] [PDF]
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R. S. Abraham, R. J. Clark, S. C. Bryant, J. F. Lymp, T. Larson, R. A. Kyle, and J. A. Katzmann Correlation of Serum Immunoglobulin Free Light Chain Quantification with Urinary Bence Jones Protein in Light Chain Myeloma Clin. Chem., April 1, 2002; 48(4): 655 - 657. [Full Text] [PDF]
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M. A. Hussein Nontraditional Cytotoxic Therapies for Relapsed/Refractory Multiple Myeloma Oncologist, April 1, 2002; 7(90001): 20 - 29. [Abstract] [Full Text] [PDF]
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 B. P. O'Connor, M. Cascalho, and R. J. Noelle Short-lived and Long-lived Bone Marrow Plasma Cells Are Derived from a Novel Precursor Population J. Exp. Med., March 18, 2002; 195(6): 737 - 745. [Abstract] [Full Text] [PDF]
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B. Zhang, I. Gojo, and R. G. Fenton Myeloid cell factor-1 is a critical survival factor for multiple myeloma Blood, March 15, 2002; 99(6): 1885 - 1893. [Abstract] [Full Text] [PDF]
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F. Zhan, J. Hardin, B. Kordsmeier, K. Bumm, M. Zheng, E. Tian, R. Sanderson, Y. Yang, C. Wilson, M. Zangari, et al. Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells Blood, March 1, 2002; 99(5): 1745 - 1757. [Abstract] [Full Text] [PDF]
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P. W. B. Derksen, R. M. J. Keehnen, L. M. Evers, M. H. J. van Oers, M. Spaargaren, and S. T. Pals Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma Blood, February 15, 2002; 99(4): 1405 - 1410. [Abstract] [Full Text] [PDF]
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K. C. Anderson, J. D. Shaughnessy Jr., B. Barlogie, J.-L. Harousseau, and G. D. Roodman Multiple Myeloma Hematology, January 1, 2002; 2002(1): 214 - 240. [Abstract] [Full Text]
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M. M. Oshiro, T. H. Landowski, R. Catlett-Falcone, L. A. Hazlehurst, M. Huang, R. Jove, and W. S. Dalton Inhibition of JAK Kinase Activity Enhances Fas-mediated Apoptosis but Reduces Cytotoxic Activity of Topoisomerase II Inhibitors in U266 Myeloma Cells Clin. Cancer Res., December 1, 2001; 7(12): 4262 - 4271. [Abstract] [Full Text] [PDF]
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Y. Aoki, M. Narazaki, T. Kishimoto, and G. Tosato Receptor engagement by viral interleukin-6 encoded by Kaposi sarcoma-associated herpesvirus Blood, November 15, 2001; 98(10): 3042 - 3049. [Abstract] [Full Text] [PDF]
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T. Reiman, K. Seeberger, B. J. Taylor, A. J. Szczepek, J. Hanson, M. J. Mant, R. W. Coupland, A. R. Belch, and L. M. Pilarski Persistent preswitch clonotypic myeloma cells correlate with decreased survival: evidence for isotype switching within the myeloma clone Blood, November 1, 2001; 98(9): 2791 - 2799. [Abstract] [Full Text] [PDF]
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Q. Chen, B. Gong, A. S. Mahmoud-Ahmed, A. Zhou, E. D. Hsi, M. Hussein, and A. Almasan Apo2L/TRAIL and Bcl-2-related proteins regulate type I interferon-induced apoptosis in multiple myeloma Blood, October 1, 2001; 98(7): 2183 - 2192. [Abstract] [Full Text] [PDF]
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N. V. Smadja, C. Bastard, C. Brigaudeau, D. Leroux, and C. Fruchart Hypodiploidy is a major prognostic factor in multiple myeloma Blood, October 1, 2001; 98(7): 2229 - 2238. [Abstract] [Full Text] [PDF]
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S. R. Hayman, R. J. Bailey, S. M. Jalal, G. J. Ahmann, A. Dispenzieri, M. A. Gertz, P. R. Greipp, R. A. Kyle, M. Q. Lacy, S. V. Rajkumar, et al. Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis Blood, October 1, 2001; 98(7): 2266 - 2268. [Abstract] [Full Text] [PDF]
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R. N. Pearse, E. M. Sordillo, S. Yaccoby, B. R. Wong, D. F. Liau, N. Colman, J. Michaeli, J. Epstein, and Y. Choi Multiple myeloma disrupts the TRANCE/ osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression PNAS, September 13, 2001; (2001) 201394498. [Abstract] [Full Text] [PDF]
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 A. A. Zaidi and D. H. Vesole Multiple Myeloma: An Old Disease with New Hope for the Future CA Cancer J Clin, September 1, 2001; 51(5): 273 - 285. [Abstract] [Full Text] [PDF]
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N. Kalakonda, D. G. Rothwell, J. H. Scarffe, and J. D. Norton Detection of N-Ras codon 61 mutations in subpopulations of tumor cells in multiple myeloma at presentation Blood, September 1, 2001; 98(5): 1555 - 1560. [Abstract] [Full Text] [PDF]
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J. De Vos, G. Couderc, K. Tarte, M. Jourdan, G. Requirand, M.-C. Delteil, J.-F. Rossi, N. Mechti, and B. Klein Identifying intercellular signaling genes expressed in malignant plasma cells by using complementary DNA arrays Blood, August 1, 2001; 98(3): 771 - 780. [Abstract] [Full Text] [PDF]
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J. M. Grad, N. J. Bahlis, I. Reis, M. M. Oshiro, W. S. Dalton, and L. H. Boise Ascorbic acid enhances arsenic trioxide-induced cytotoxicity in multiple myeloma cells Blood, August 1, 2001; 98(3): 805 - 813. [Abstract] [Full Text] [PDF]
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K. Podar, Y.-T. Tai, F. E. Davies, S. Lentzsch, M. Sattler, T. Hideshima, B. K. Lin, D. Gupta, Y. Shima, D. Chauhan, et al. Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration Blood, July 15, 2001; 98(2): 428 - 435. [Abstract] [Full Text] [PDF]
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J. Shaughnessy Jr, A. Gabrea, Y. Qi, L. Brents, F. Zhan, E. Tian, J. Sawyer, B. Barlogie, P. L. Bergsagel, and M. Kuehl Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma Blood, July 1, 2001; 98(1): 217 - 223. [Abstract] [Full Text] [PDF]
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G. Guillerm, E. Gyan, D. Wolowiec, T. Facon, H. Avet-Loiseau, K. Kuliczkowski, F. Bauters, P. Fenaux, and B. Quesnel p16INK4a and p15INK4b gene methylations in plasma cells from monoclonal gammopathy of undetermined significance Blood, July 1, 2001; 98(1): 244 - 246. [Abstract] [Full Text] [PDF]
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V. Perfetti, A. M. L. Coluccia, D. Intini, U. Malgeri, M. C. Vignarelli, S. Casarini, G. Merlini, and A. Neri Translocation t(4;14)(p16.3;q32) Is a Recurrent Genetic Lesion in Primary Amyloidosis Am. J. Pathol., May 1, 2001; 158(5): 1599 - 1603. [Abstract] [Full Text] [PDF]
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Z. Li, Y. X. Zhu, E. E. Plowright, P. L. Bergsagel, M. Chesi, B. Patterson, T. S. Hawley, R. G. Hawley, and A. K. Stewart The myeloma-associated oncogene fibroblast growth factor receptor 3 is transforming in hematopoietic cells Blood, April 15, 2001; 97(8): 2413 - 2419. [Abstract] [Full Text] [PDF]
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T. Hideshima, P. Richardson, D. Chauhan, V. J. Palombella, P. J. Elliott, J. Adams, and K. C. Anderson The Proteasome Inhibitor PS-341 Inhibits Growth, Induces Apoptosis, and Overcomes Drug Resistance in Human Multiple Myeloma Cells Cancer Res., April 1, 2001; 61(7): 3071 - 3076. [Abstract] [Full Text]
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F. De Benedetti, P. Pignatti, M. Vivarelli, C. Meazza, G. Ciliberto, R. Savino, and A. Martini In Vivo Neutralization of Human IL-6 (hIL-6) Achieved by Immunization of hIL-6-Transgenic Mice with a hIL-6 Receptor Antagonist J. Immunol., April 1, 2001; 166(7): 4334 - 4340. [Abstract] [Full Text] [PDF]
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M. Chesi, L. A. Brents, S. A. Ely, C. Bais, D. F. Robbiani, E. A. Mesri, W. M. Kuehl, and P. L. Bergsagel Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma Blood, February 1, 2001; 97(3): 729 - 736. [Abstract] [Full Text] [PDF]
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F. Sanz-Rodriguez, A. Hidalgo, and J. Teixido Chemokine stromal cell-derived factor-1{alpha} modulates VLA-4 integrin-mediated multiple myeloma cell adhesion to CS-1/fibronectin and VCAM-1 Blood, January 15, 2001; 97(2): 346 - 351. [Abstract] [Full Text] [PDF]
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M. A. Frassanito, A. Cusmai, G. Iodice, and F. Dammacco Autocrine interleukin-6 production and highly malignant multiple myeloma: relation with resistance to drug-induced apoptosis Blood, January 15, 2001; 97(2): 483 - 489. [Abstract] [Full Text] [PDF]
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P. J. Ho, R. D. Brown, G. J. Pelka, A. Basten, J. Gibson, and D. E. Joshua Illegitimate switch recombinations are present in approximately half of primary myeloma tumors, but do not relate to known prognostic indicators or survival Blood, January 15, 2001; 97(2): 490 - 495. [Abstract] [Full Text] [PDF]
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O. Hjertner, H. Hjorth-Hansen, M. Borset, C. Seidel, A. Waage, and A. Sundan Bone morphogenetic protein-4 inhibits proliferation and induces apoptosis of multiple myeloma cells Blood, January 15, 2001; 97(2): 516 - 522. [Abstract] [Full Text] [PDF]
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Y.-T. Tai, G. Teoh, B. Lin, F. E. Davies, D. Chauhan, S. P. Treon, N. Raje, T. Hideshima, Y. Shima, K. Podar, et al. Ku86 Variant Expression and Function in Multiple Myeloma Cells Is Associated with Increased Sensitivity to DNA Damage J. Immunol., December 1, 2000; 165(11): 6347 - 6355. [Abstract] [Full Text] [PDF]
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Introduction
References
untranslated region of the c-myc
gene leading to a deregulated translational control of c-myc gene
expression.
or
CD38++CD49E+) appear to express the same clonal
idiotype as mature cells (CD38++CD45
S transition in the cell cycle by inhibiting
E2F-mediated transactivation of a variety of genes involved in
initiating DNA synthesis, such as c-myc, b-myb, cdc2, dihydrofolate
reductase, and thymidine kinase.
, MPC
Introduction
A study of 151 patients including 117 patients at diagnosis.
Blood
85:2490,
1995