Myeloma - Molecular Biology

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Immunoglobulin Heavy Chains
  • Mutation
  • MicroRNAs
  • Gene Expression Profiling
  • Proto-Oncogene Proteins c-myc
  • RT-PCR
  • Chromosome Aberrations
  • Monoclonal Gammopathy of Undetermined Significance
  • Disease-Free Survival
  • Gene Expression
  • Case-Control Studies
  • Cytogenetic Analysis
  • Chromosome 1
  • Recurrence
  • Recombinant Proteins
  • MAF
  • Cancer Gene Expression Regulation
  • Single Nucleotide Polymorphism
  • Disease Progression
  • Neoplasm Proteins
  • Genotype
  • Tunisia
  • Chromosome 14
  • Genetic Predisposition
  • Drug Resistance
  • FISH
  • CIC
  • Cell Proliferation
  • DKK1
  • NFKB1
  • Staging
  • DNA Methylation
  • Tumor Markers
  • Multiple Myeloma
  • CCND2
  • Chromosome Deletion
  • BIRC3
  • Up-Regulation
  • Cell Survival
  • Boronic Acids
  • Antineoplastic Agents
  • Bone Marrow
  • SDC1
  • Venous Thromboembolism
  • Karyotyping
  • Apoptosis
Tag cloud generated 04 January, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (78)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

IGH 14q32.33 IGD1, IGH@, IGHJ, IGHV, IGHD@, IGHJ@, IGHV@, IGH.1@, IGHDY1 Translocation
-t(6;14)(p25;q32) in Myeloma
-IGH and Multiple Myeloma
TNFRSF11B 8q24 OPG, TR1, OCIF -TNFRSF11B and Multiple Myeloma
FGFR3 4p16.3 ACH, CEK2, JTK4, CD333, HSFGFR3EX -FGFR3 and Multiple Myeloma
TNFRSF11A 18q22.1 FEO, OFE, ODFR, OSTS, PDB2, RANK, CD265, OPTB7, TRANCER, LOH18CR1 -TNFRSF11A and Multiple Myeloma
MAF 16q22-q23 CCA4, c-MAF -MAF and Multiple Myeloma
CD19 16p11.2 B4, CVID3 -CD19 and Multiple Myeloma
SDC1 2p24.1 SDC, CD138, SYND1, syndecan -SDC1 and Multiple Myeloma
WHSC1 4p16.3 WHS, NSD2, TRX5, MMSET, REIIBP -WHSC1 and Multiple Myeloma
DKK1 10q11.2 SK, DKK-1 -DKK1 and Multiple Myeloma
IFNA7 9p22 IFNA-J, IFN-alphaJ -IFNA7 and Multiple Myeloma
IFNA17 9p22 IFNA, INFA, LEIF2C1, IFN-alphaI -IFNA17 and Multiple Myeloma
CCND2 12p13 MPPH3, KIAK0002 -CCND2 and Multiple Myeloma
IFNA2 9p22 IFNA, INFA2, IFNA2B, IFN-alphaA -IFNA2 and Multiple Myeloma
TNFSF11 13q14 ODF, OPGL, sOdf, CD254, OPTB2, RANKL, TRANCE, hRANKL2 -TNFSF11 and Multiple Myeloma
IGL 22q11.2 IGL@, IGLC6 -IGL and Multiple Myeloma
CCND3 6p21 -CCND3 and Multiple Myeloma
CCL3 17q12 MIP1A, SCYA3, G0S19-1, LD78ALPHA, MIP-1-alpha -CCL3 and Multiple Myeloma
CKS1B 1q21.2 CKS1, ckshs1, PNAS-16, PNAS-18 -CKS1B and Multiple Myeloma
NFKB1 4q24 p50, KBF1, p105, EBP-1, NF-kB1, NFKB-p50, NFkappaB, NF-kappaB, NFKB-p105, NF-kappa-B -NFKB1 and Multiple Myeloma
IGK 2p12 IGK@ -IGK and Multiple Myeloma
PRDM1 6q21 BLIMP1, PRDI-BF1 -PRDM1 and Multiple Myeloma
IRF4 6p25-p23 MUM1, LSIRF, SHEP8, NF-EM5 Translocation
-t(6;14)(p25;q32) in Myeloma
TNFRSF17 16p13.1 BCM, BCMA, CD269, TNFRSF13A -TNFRSF17 and Multiple Myeloma
CD27 12p13 T14, S152, Tp55, TNFRSF7, S152. LPFS2 -CD27 and Multiple Myeloma
CIC 19q13.2 -CIC and Multiple Myeloma
MUM1 19p13.3 MUM-1, EXPAND1, HSPC211 -MUM1 and Multiple Myeloma
B2M 15q21-q22.2 -B2M and Multiple Myeloma
XBP1 22q12.1 XBP2, TREB5, XBP-1 -XBP1 and Multiple Myeloma
TRAF3 14q32.32 CAP1, LAP1, CAP-1, CRAF1, IIAE5, CD40bp -TRAF3 and Multiple Myeloma
THRA 17q11.2 AR7, EAR7, ERBA, CHNG6, ERBA1, NR1A1, THRA1, THRA2, ERB-T-1, c-ERBA-1 -THRA and Multiple Myeloma
NFKB2 10q24 p52, p100, H2TF1, LYT10, CVID10, LYT-10, NF-kB2 -NFKB2 and Multiple Myeloma
BIRC3 11q22 AIP1, API2, MIHC, CIAP2, HAIP1, HIAP1, MALT2, RNF49, c-IAP2 -BIRC3 and Multiple Myeloma
IL6ST 5q11.2 CD130, GP130, CDW130, IL-6RB -IL6ST and Multiple Myeloma
CCL4 17q12 ACT2, G-26, HC21, LAG1, LAG-1, MIP1B, SCYA2, SCYA4, MIP1B1, AT744.1, MIP-1-beta -CCL4 and Multiple Myeloma
TNFSF13B 13q32-q34 DTL, BAFF, BLYS, CD257, TALL1, THANK, ZTNF4, TALL-1, TNFSF20 -TNFSF13B and Multiple Myeloma
SCFV 14 -SCFV and Multiple Myeloma
GALM 2p22.1 GLAT, IBD1, BLOCK25, HEL-S-63p -GALM and Multiple Myeloma
FRZB 2q32.1 FRE, OS1, FZRB, hFIZ, FRITZ, FRP-3, FRZB1, SFRP3, SRFP3, FRZB-1, FRZB-PEN -FRZB and Multiple Myeloma
CDR2 16p12.3 Yo, CDR62 -CDR2 and Multiple Myeloma
CYP2C8 10q23.33 CPC8, CYPIIC8, MP-12/MP-20 -CYP2C8 and Multiple Myeloma
ITGA4 2q31.3 IA4, CD49D -ITGA4 and Multiple Myeloma
HAS1 19q13.4 HAS -HAS1 and Multiple Myeloma
FAS 10q24.1 APT1, CD95, FAS1, APO-1, FASTM, ALPS1A, TNFRSF6 -FAS and Multiple Myeloma
TACC3 4p16.3 ERIC1, ERIC-1 -TACC3 and Multiple Myeloma
CD52 1p36 CDW52 -CD52 and Multiple Myeloma
MBL2 10q11.2 MBL, MBP, MBP1, MBPD, MBL2D, MBP-C, COLEC1, HSMBPC -MBL2 and Multiple Myeloma
BCL9 1q21 LGS -BCL9 and Multiple Myeloma
CD58 1p13 ag3, LFA3, LFA-3 -CD58 and Multiple Myeloma
CD81 11p15.5 S5.7, CVID6, TAPA1, TSPAN28 -CD81 and Multiple Myeloma
NR3C1 5q31.3 GR, GCR, GRL, GCCR, GCRST -NR3C1 and Multiple Myeloma
ITGAL 16p11.2 CD11A, LFA-1, LFA1A -ITGAL and Multiple Myeloma
CD200 3q13.2 MRC, MOX1, MOX2, OX-2 -CD200 and Multiple Myeloma
JAG2 14q32 HJ2, SER2 -JAG2 and Multiple Myeloma
IL6R 1q21 IL6Q, gp80, CD126, IL6RA, IL6RQ, IL-6RA, IL-6R-1 -IL6R and Multiple Myeloma
FAM46C 1p12 -FAM46C and Multiple Myeloma
BIRC2 11q22 API1, MIHB, HIAP2, RNF48, cIAP1, Hiap-2, c-IAP1 -BIRC2 and Multiple Myeloma
TLR1 4p14 TIL, CD281, rsc786, TIL. LPRS5 -TLR1 and Multiple Myeloma
BAGE 21p11.1 BAGE1, CT2.1 -BAGE and Multiple Myeloma
IL21 4q26-q27 Za11, IL-21, CVID11 -IL21 and Multiple Myeloma
PIAS3 1q21 ZMIZ5 -PIAS3 and Multiple Myeloma
TLR7 Xp22.3 TLR7-like -TLR7 and Multiple Myeloma
PCDH10 4q28.3 PCDH19, OL-PCDH -PCDH10 and Multiple Myeloma
NFATC1 18q23 NFAT2, NFATc, NF-ATC -NFATC1 and Multiple Myeloma
PDCD5 19q13.11 TFAR19 -PDCD5 and Multiple Myeloma
POU2AF1 11q23.1 BOB1, OBF1, OCAB, OBF-1 -POU2AF1 and Multiple Myeloma
BACH2 6q15 BTBD25 -BACH2 and Multiple Myeloma
TNFSF13 17p13.1 APRIL, CD256, TALL2, ZTNF2, TALL-2, TRDL-1, UNQ383/PRO715 -TNFSF13 and Multiple Myeloma
FCGR2A 1q23 CD32, FCG2, FcGR, CD32A, CDw32, FCGR2, IGFR2, FCGR2A1 -FCGR2A and Multiple Myeloma
ADAMTS9 3p14.1 -ADAMTS9 and Multiple Myeloma
RNF217-AS1 6q22.33 STL -STL and Multiple Myeloma
CD47 3q13.1-q13.2 IAP, OA3, MER6 -CD47 and Multiple Myeloma
KL 13q12 -KL and Multiple Myeloma
SLAMF1 1q23.3 SLAM, CD150, CDw150 -SLAMF1 and Multiple Myeloma
CD1D 1q23.1 R3, CD1A -CD1D and Multiple Myeloma
TRIM13 13q14 CAR, LEU5, RFP2, DLEU5, RNF77 -TRIM13 and Multiple Myeloma
SRPX Xp21.1 DRS, ETX1, SRPX1, HEL-S-83p -SRPX and Multiple Myeloma
ZNF331 19q13.42 RITA, ZNF361, ZNF463 -ZNF331 and Multiple Myeloma
MAFB 20q11.2-q13.1 KRML, MCTO Translocation
-Occasional translocation of MAFB in Myeloma
-MAFB overexpresed in Myeloma

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

Li B, Chen P, Qu J, et al.
Activation of LTBP3 gene by a long noncoding RNA (lncRNA) MALAT1 transcript in mesenchymal stem cells from multiple myeloma.
J Biol Chem. 2014; 289(42):29365-75 [PubMed] Article available free on PMC after 17/10/2015 Related Publications
Long noncoding RNAs (lncRNAs) are emerging as important regulatory molecules in tumor suppressor and oncogenic pathways. However, the magnitude of the contribution of lncRNA expression to normal human tissues and cancers has not been investigated in a comprehensive manner. Here we explored the biology of the lncRNA MALAT1 and considered the potential significance in mesenchymal stem cells from myeloma patients. By using assays such as RNA interference, luciferase, chromatin immunoprecipitation, and RNA immunoprecipitation, we showed that in mesenchymal stem cells MALAT1 promoted the activation effect of the key transcription factor Sp1 on LTBP3 promoter by modulating recruitment of Sp1 to the LTBP3 gene that regulated the bioavailability of TGF-β in particular. Our data suggested that lncRNA MALAT1 directly interacted with Sp1 and LTBP3 promoter to increase expression of LTBP3 gene. The specificity and efficiency of activation were ensured by the formation of a stable complex between MALAT1 and the LTBP3 promoter, direct interaction of MALAT1 with Sp1, and recruitment of Sp1 to the promoter. In this study, we showed that the mechanism of transcriptional activation of LTBP3 promoter depended on MALAT1 initiated from neighboring gene LTBP3 and involved both the direct interaction of the Sp1 and promoter-specific activation. Our knowledge of the role of MALAT1 in cellular transformation is pointing toward its potential use as a biomarker and a target for novel therapeutic approaches in multiple myeloma.

Related: MALAT1

Neemat K, Rania K, Tarek M, Hamdy AA
Effect of 13q deletion on IL-6 production in patients with multiple myeloma: a hypothesis may hold true.
Clin Lab. 2014; 60(8):1393-9 [PubMed] Related Publications
BACKGROUND: Numerous studies have shown a correlation between 13q deletion and poor prognosis in multiple myeloma (MM), but the mechanisms are not fully understood. Earlier studies suggest that this lesion involves large segments or the entire long arm involving the retinoblastoma (Rb) gene. In myeloma, Rb gene is believed to down regulate interleukin-6 (IL-6) which plays a central role in the pathogenesis of MM. Therefore, it has been hypothesized that loss of the Rb gene might be associated with very high expression of IL-6 and subsequent bad prognosis. Hence this study evaluates IL-6 production in MM patients with and without 13q deletions and assesses their response to conventional and new therapeutic regimens.
METHODS: Forty MM patients and 20 matched controls were included in this study. Interphase fluorescence in situ hybridization (FISH) analysis was performed using LSI 13q14-specific probe. Serum levels of IL-6 were determined by ELISA. All patients received conventional chemotherapy. Refractory patients received other therapeutic regimens of Thalidomide or Bortezomib.
RESULTS: Significant increase (p < 0.001) of IL-6 production was recorded in patients with a 13q deletion compared to patients with normal chromosome 13q status. These patients were also refractory to conventional chemotherapy but showed striking response to Thalidomide or Bortezomib.
CONCLUSIONS: This study suggests that 13q deletions are associated with increased production of IL-6 in MM and this could be a possible cause of the associated bad prognosis. In addition, the results also show the potential to improve responses in patients with refractory MM with the introduction of novel therapies.

Related: Chromosome 13 FISH Thalidomide Bortezomib

Li Y, Li D, Yan Z, et al.
Potential relationship and clinical significance of miRNAs and Th17 cytokines in patients with multiple myeloma.
Leuk Res. 2014; 38(9):1130-5 [PubMed] Related Publications
We evaluated the potential relationship between miRNAs and Th17 cytokines in multiple myeloma (MM) patients. Twenty-seven newly diagnosed myeloma patients and eight normal donors were studied. We determined that the relative expression levels of miR-15a/16, miR-34a, miR-194 in MM patients were significantly lower than those in the healthy controls with exception for miR-181a/b, which showed significantly higher in MM patients (P<0.05). In contrast, the levels of IL-17, IL-21 and IL-27 were up-regulated in MM patients compared to healthy controls while IL-22 was down-regulated (P<0.05). The expression patterns of them were differentially present in various groups according to the International Staging System (ISS) criteria. Up-regulated IL-17, IL-21 and IL-27 may potentially down-regulate the expression of several miRNAs in MM patients. Establishment of the relationship may be useful for understanding the pathogenesis of MM and for clinical diagnosis of the disease.

Related: Cytokines

Johnson SK, Stewart JP, Bam R, et al.
CYR61/CCN1 overexpression in the myeloma microenvironment is associated with superior survival and reduced bone disease.
Blood. 2014; 124(13):2051-60 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
Secreted protein CCN1, encoded by CYR61, is involved in wound healing, angiogenesis, and osteoblast differentiation. We identified CCN1 as a microenvironmental factor produced by mesenchymal cells and overexpressed in bones of a subset of patients with monoclonal gammopathy of undetermined significance (MGUS), asymptomatic myeloma (AMM), and multiple myeloma (MM). Our analysis showed that overexpression of CYR61 was independently associated with superior overall survival of MM patients enrolled in our Total Therapy 3 protocol. Moreover, elevated CCN1 was associated with a longer time for MGUS/AMM to progress to overt MM. During remission from MM, high levels of CCN1 were associated with superior progression-free and overall survival and stratified patients with molecularly defined high-risk MM. Recombinant CCN1 directly inhibited in vitro growth of MM cells, and overexpression of CYR61 in MM cells reduced tumor growth and prevented bone destruction in vivo in severe combined immunodeficiency-hu mice. Signaling through αvβ3 was required for CCN1 prevention of bone disease. CYR61 expression may signify early perturbation of the microenvironment before conversion to overt MM and may be a compensatory mechanism to control MM progression. Therapeutics that upregulate CYR61 should be investigated for treating MM bone disease.

Xiong T, Wei H, Chen X, Xiao H
[Effect of PARP1 inhibitor PJ34 on multi-drug resistance in human multiple myeloma cell line and its relationship with FA/BRCA pathway].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2014; 31(3):312-6 [PubMed] Related Publications
OBJECTIVE: To investigate the effect of PARP1 inhibitor PJ34 on multi-drug resistance in a human multiple myeloma cell line and its connection with FA/BRCA pathway in DNA damage repair.
METHODS: A CCK8 assay was used to measure the inhibition rate. Real-time quantitative PCR was used to detect expression changes of DNA repair genes involved in the FA/BRCA pathway. Western blotting assay was used to detect expression of key protein FANCD2 in the FA/BRCA pathway. Annexin VFITC/PI double staining flow cytometry was used to measure cell apoptosis induced by PJ34. A COMET assay was used to detect the effect of PJ34 on DNA damage repair.
RESULTS: PJ34 could significantly enhance the sensitivity of RPMI8226/R cells to melphalan. The IC50 value of melphalan was dropped from 20.43 mol/L to 7.8 mol/L. PJ34 could inhibit the DNA damage repair, and the effect was related with the inhibition of FA/BRCA pathway. PJ34 and melphalan showed a synergistic effect in promoting the apoptosis of RPMI8226/R cells.
CONCLUSION: PJ34 can reverse the resistance of RPMI8226/R cells to melphalan by inhibiting the FA/BRCA pathway, which in turn can induce suppression of DNA damage repair. Therefore, PJ34 may have clinical value in overcoming the multi-drug resistance of multiple myeloma.

Related: FANCD2 PARP1

Wang X, Zhu YB, Cui HP, Yu TT
Aberrant promoter methylation of p15 (INK⁴b) and p16 (INK⁴a) genes may contribute to the pathogenesis of multiple myeloma: a meta-analysis.
Tumour Biol. 2014; 35(9):9035-43 [PubMed] Related Publications
We carried out the current meta-analysis aiming to comprehensively assess the potential role of p15 (INK4b) and p16 (INK4a) aberrant promoter methylation in the pathogenesis of multiple myeloma (MM). The MEDLINE (1966 ~ 2013), Cochrane Library (Issue 12, 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), Web of Science (1945 ~ 2013), and Chinese Biomedical (CBM) (1982 ~ 2013) databases were searched without language restrictions. Meta-analyses were conducted using Stata software (Version 12.0, Stata Corporation, College Station, TX, USA). Odds ratios (ORs) and their 95 % confidence intervals (95 %CIs) were calculated. Thirteen clinical case-control studies, which enrolled a total of 465 MM patients and 180 healthy subjects, were included in the meta-analysis. The results of our meta-analysis demonstrated that the frequencies of p15 (INK4b) and p16 (INK4a) promoter methylation in cancer samples were significantly higher than in normal samples (p15 (INK4b) : OR = 6.26, 95 %CI = 3.87 ~ 10.12, P < 0.001; p16 (INK4a) : OR = 2.26, 95 %CI = 1.22 ~ 4.20, P < 0.001). Ethnicity-stratified analysis showed that the aberrant methylation of p15 (INK4b) was significantly related with the risk of MM among both Caucasians and Asians (all P < 0.05). Furthermore, our results also illustrated a strong positive correlation between p16 (INK4a) promoter methylation and the pathogenesis of MM among Asians (OR = 5.17, 95 %CI = 3.45 ~ 7.74, P < 0.001), but not among Caucasians (P > 0.05). The current meta-analysis confirms and reinforces existing findings that p15 (INK4b) and p16 (INK4a) promoter methylation may be closely implicated in the pathogenesis of MM.

Wen J, Li H, Tao W, et al.
High throughput quantitative reverse transcription PCR assays revealing over-expression of cancer testis antigen genes in multiple myeloma stem cell-like side population cells.
Br J Haematol. 2014; 166(5):711-9 [PubMed] Related Publications
Multiple myeloma (MM) stem cells, proposed to be responsible for the tumourigenesis, drug resistance and recurrence of this disease, are enriched in the cancer stem cell-like side population (SP). Cancer testis antigens (CTA) are attractive targets for immunotherapy because they are widely expressed in cancers but only in limited types of normal tissues. We designed a high throughput assay, which allowed simultaneous relative quantifying expression of 90 CTA genes associated with MM. In the three MM cell lines tested, six CTA genes were over-expressed in two and LUZP4 and ODF1 were universally up-regulated in all three cell lines. Subsequent study of primary bone marrow (BM) from eight MM patients and four healthy donors revealed that 19 CTA genes were up-regulated in SP of MM compared with mature plasma cells. In contrast, only two CTA genes showed a moderate increase in SP cells of healthy BM. Furthermore, knockdown using small interfering RNA (siRNA) revealed that LUZP4 expression is required for colony-forming ability and drug resistance in MM cells. Our findings indicate that multiple CTA have unique expression profiles in MM SP, suggesting that CTA may serve as targets for immunotherapy that it specific for MM stem cells and which may lead to the long-term cure of MM.

Related: Apoptosis

Moreau P, Cavo M, Sonneveld P, et al.
Combination of international scoring system 3, high lactate dehydrogenase, and t(4;14) and/or del(17p) identifies patients with multiple myeloma (MM) treated with front-line autologous stem-cell transplantation at high risk of early MM progression-related death.
J Clin Oncol. 2014; 32(20):2173-80 [PubMed] Related Publications
PURPOSE: To construct and validate among patients with multiple myeloma (MM) who were treated with intensive therapy a prognostic index of early MM progression-related death.
PATIENTS AND METHODS: Patient-level data from the Intergroupe Francophone du Myélome (IFM) 2005-01 trial (N = 482) were used to construct the prognostic index. The event was MM progression-related death within 2 years from treatment initiation. The index was validated using data from three other trials: the Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) 26866138-MMY-3006 trial (N = 480), the Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA)-GEMMENOS65 trial (N = 390), and the Hemato-Oncologie voor Volwassenen Nederland (HOVON) -65/German-Speaking Myeloma Multicenter Group (GMMG) -HD4 trial (N = 827).
RESULTS: The risk of early MM progression-related death was related to three independent prognostic variables: lactate dehydrogenase (LDH) higher than than normal, International Staging System 3 (ISS3), and adverse cytogenetics [t(4;14) and/or del(17p)]. These three variables enabled the definition of an ordinal prognostic classification composed of four scores (0 to 3). Patients with a score of 3, defined by the presence of t(4;14) and/or del(17p) in addition to ISS3 and/or high LDH, comprised 5% (20 of 387 patients) to 8% (94 of 1,139 patients) of the patients in the learning and validation samples, respectively, and they had a very poor prognosis. When applied to the population of 855 patients who had received bortezomib-based induction therapy in the four trials, the prognostic classification was also able to segregate patients into four categories, with a very poor prognosis attributed to patients with a score of 3.
CONCLUSION: Our model allows the simple definition of a subgroup of MM patients at high risk of early MM progression-related death despite the use of the most modern and effective strategies.

Related: Chromosome 14 Chromosome 17 Chromosome 4

van Laar R, Flinchum R, Brown N, et al.
Translating a gene expression signature for multiple myeloma prognosis into a robust high-throughput assay for clinical use.
BMC Med Genomics. 2014; 7:25 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
BACKGROUND: Widespread adoption of genomic technologies in the management of heterogeneous indications, including Multiple Myeloma, has been hindered by concern over variation between published gene expression signatures, difficulty in physician interpretation and the challenge of obtaining sufficient genetic material from limited patient specimens.
METHODS: Since 2006, the 70-gene prognostic signature, developed by the University of Arkansas for Medical Sciences (UAMS) has been applied to over 4,700 patients in studies performed in 4 countries and described in 17 peer-reviewed publications. Analysis of control sample and quality control data compiled over a 12-month period was performed.
RESULTS: Over a 12 month period, the 70-gene prognosis score (range 0-100) of our multiple myeloma cell-line control sample had a standard deviation of 2.72 and a coefficient of variance of 0.03. The whole-genome microarray profile used to calculate a patient's GEP70 score can be generated with as little as 15 ng of total RNA; approximately 30,000 CD-138+ plasma cells. Results from each GEP70 analysis are presented as either low (70-gene score <45.2) or high (≥45.2) risk for relapse (newly diagnosed setting) or shorter overall survival (relapse setting). A personalized and outcome-annotated gene expression heat map is provided to assist in the clinical interpretation of the result.
CONCLUSIONS: The 70-gene assay, commercialized under the name 'MyPRS®' (Myeloma Prognostic Risk Score) and performed in Signal Genetics' CLIA-certified high throughput flow-cytometry and molecular profiling laboratory is a reproducible and standardized method of multiple myeloma prognostication.

Yuan L, Chan GC, Fung KL, Chim CS
RANKL expression in myeloma cells is regulated by a network involving RANKL promoter methylation, DNMT1, microRNA and TNFα in the microenvironment.
Biochim Biophys Acta. 2014; 1843(9):1834-8 [PubMed] Related Publications
We studied the regulation of RANKL expression in myeloma by promoter DNA methylation. Methylation-specific polymerase chain reaction showed complete methylation of RANKL promoter in WL-2 myeloma cells but partial methylation in eight other lines. 5-AzadC treatment of WL-2 cells led to demethylation and re-expression of RANKL. Transwell and contact co-culture of WL-2 cells with normal bone marrow-derived mesenchymal stromal cells (BMSCs) resulted in comparable repression of DNA methyltransferase-1 (DNMT1) and re-expression of RANKL in WL-2 cells. Moreover, treatment of WL-2 cells with TNFα led to repression of DNMT1 and re-expression of RANKL in association with upregulation of miR-140-3p and miR-126, which are partially offset by addition of anti-TNFα antibody to transwell-coculture of WL2 with BMSC. Taken together, our results showed that TNFα in the marrow microenvironment led to RANKL demethylation and re-expression in myeloma cells through DNMT1 repression and upregulation of miR-126-3p and miR-140, both known to repress DNMT1 translation.

Related: TNF

Abe M
[Cytokines and myeloma bone disease].
Clin Calcium. 2014; 24(6):871-8 [PubMed] Related Publications
Multiple myeloma (MM) develops and expands almost exclusively in the bone marrow, and generates devastating bone destruction. MM cells produce a variety of cytokines to stimulate RANK ligand-mediated osteoclastogenesis and suppress osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone. MM cells alter through bone destruction the microenvironment in bone where they colonize, which in turn favors tumor growth and survival, thereby forming a progressive vicious cycle between tumor expansion and bone destruction in MM.

Related: Cytokines DKK1

Lonial S, Gleason C
Down to the bitter end.
Blood. 2014; 123(20):3061-2 [PubMed] Related Publications
"The daintiest last, to make the end most sweet," comes to us from Shakespeare’s Richard II, but in the most recent edition of Blood, the paper from Martinez-Lopez et al suggests that by using minimal residual disease (MRD) testing by sequencing, we may be nearing the "end most sweet" or, in 21st century vernacular, the cure of myeloma.

Leotta M, Biamonte L, Raimondi L, et al.
A p53-dependent tumor suppressor network is induced by selective miR-125a-5p inhibition in multiple myeloma cells.
J Cell Physiol. 2014; 229(12):2106-16 [PubMed] Related Publications
The analysis of deregulated microRNAs (miRNAs) is emerging as a novel approach to disclose the regulation of tumor suppressor or tumor promoting pathways in tumor cells. Targeting aberrantly expressed miRNAs is therefore a promising strategy for cancer treatment. By miRNA profiling of primary plasma cells from multiple myeloma (MM) patients, we previously reported increased miR-125a-5p levels associated to specific molecular subgroups. On these premises, we aimed at investigating the biological effects triggered by miR-125a-5p modulation in MM cells. Expression of p53 pathway-related genes was down-regulated in MM cells transfected with miR-125a-5p mimics. Luciferase reporter assays confirmed specific p53 targeting at 3'UTR level by miR-125a-5p mimics. Interestingly, bone marrow stromal cells (BMSCs) affected the miR-125a-5p/p53 axis, since adhesion of MM cells to BMSCs strongly up-regulated miR-125a-5p levels, while reduced p53 expression. Moreover, ectopic miR-125a-5p reduced, while miR-125-5p inhibitors promoted, the expression of tumor suppressor miR-192 and miR-194, transcriptionally regulated by p53. Lentiviral-mediated stable inhibition of miR-125a-5p expression in wild-type p53 MM cells dampened cell growth, increased apoptosis and reduced cell migration. Importantly, inhibition of in vitro MM cell proliferation and migration was also achieved by synthetic miR-125a-5p inhibitors and was potentiated by the co-expression of miR-192 or miR-194. Taken together, our data indicate that miR-125a-5p antagonism results in the activation of p53 pathway in MM cells, underlying the crucial role of this miRNA in the biopathology of MM and providing the molecular rationale for the combinatory use of miR-125a inhibitors and miR-192 or miR-194 mimics for MM treatment.

Related: Apoptosis TP53

Khan R, Gupta N, Kumar R, et al.
Augmented expression of urokinase plasminogen activator and extracellular matrix proteins associates with multiple myeloma progression.
Clin Exp Metastasis. 2014; 31(5):585-93 [PubMed] Related Publications
Multiple myeloma (MM) represents a B cell malignancy, characterized by a monoclonal proliferation of malignant plasma cells. Interactions between tumor cells and extracellular matrix (ECM) are of importance for tumor invasion and metastasis. Protein levels of urokinase plasminogen activator (uPA) and fibulin 1, nidogen and laminin in plasma and serum respectively and mRNA levels of these molecules in peripheral blood mononuclear cells were determined in 80 subjects by using ELISA and quantitative PCR and data was analyzed with severity of disease. Pearson correlation was determined to observe interrelationship between different molecules. A statistical significant increase for ECM proteins (laminin, nidogen and fibulin 1) and uPA at circulatory level as well as at mRNA level was observed compared to healthy controls. The levels of these molecules in serum might be utilized as a marker of active disease. Significant positive correlation of all ECM proteins with uPA was found and data also correlates with severity of disease. Strong association found between ECM proteins and uPA in this study supports that there might be interplay between these molecules which can be targeted. This study on these molecules may help to gain insight into processes of growth, spread, and clinical behavior of MM.

Murray ME, Gavile CM, Nair JR, et al.
CD28-mediated pro-survival signaling induces chemotherapeutic resistance in multiple myeloma.
Blood. 2014; 123(24):3770-9 [PubMed] Article available free on PMC after 12/06/2015 Related Publications
Chemotherapeutic resistance remains a significant hurdle in the treatment of multiple myeloma (MM) and is significantly mediated by interactions between MM cells and stromal cells of the bone marrow microenvironment. Despite the importance of these interactions, the specific molecules and downstream signaling components involved remain incompletely understood. We have previously shown that the prototypic T-cell costimulatory receptor CD28, which is also expressed on MM cells, is a key mediator of MM survival and apoptotic resistance. Crosslinking CD28 by agonistic antibodies or myeloid dendritic cells (DC; these express the CD28 ligands CD80/CD86) prevents apoptosis caused by chemotherapy or serum withdrawal. We now report that CD28 pro-survival signaling is dependent upon downstream activation of phosphatidyl-inositol 3-kinase/Akt, inactivation of the transcription factor FoxO3a, and decreased expression of the pro-apoptotic molecule Bim. Conversely, blocking the CD28-CD80/CD86 interaction between MM cells and DC in vitro abrogates the DC's ability to protect MM cells against chemotherapy-induced death. Consistent with these observations, in vivo blockade of CD28-CD80/CD86 in the Vk*MYC murine myeloma model sensitizes MM cells to chemotherapy and significantly reduces tumor burden. Taken together, our findings suggest that CD28 is an important mediator of MM survival during stress and can be targeted to overcome chemotherapy resistance.

Related: AKT1 Signal Transduction

Thiele B, Kloster M, Alawi M, et al.
Next-generation sequencing of peripheral B-lineage cells pinpoints the circulating clonotypic cell pool in multiple myeloma.
Blood. 2014; 123(23):3618-21 [PubMed] Related Publications
The identity of the proliferative compartment of myeloma progenitor cells remains a matter of debate. Polymerase chain reaction-based studies suggested pre-switch "clonotypic" B cells sharing the immunoglobulin (Ig) rearrangement of the malignant plasma cell (M-PC), to circulate in the blood and possess stem cell-like properties. Here, we disprove this hypothesis. We screened peripheral blood IgM, IgG, and IgA repertoires of myeloma patients for the clonotypic rearrangement by next-generation sequencing. None of 12 cases showed pre-switch clonotypic transcripts. In the post-switch IgG/IgA repertoires, however, the clonotypic rearrangement was detected at high frequency in 6 of 8 patients with active disease, whereas it was undetectable after treatment, correlating with flow cytometric presence or absence of circulating M-PCs. Minor subclones with alternative post-switch isotypes suggested ongoing switch events and clonal evolution at the M-PC level. Our findings consistently show an absence of pre-switch clonotypic B cells, while M-PCs circulate in the peripheral blood and may contribute to spreading of the disease.

Türkmen S, Binder A, Gerlach A, et al.
High prevalence of immunoglobulin light chain gene aberrations as revealed by FISH in multiple myeloma and MGUS.
Genes Chromosomes Cancer. 2014; 53(8):650-6 [PubMed] Related Publications
Multiple myeloma (MM) is a malignant B-cell neoplasm characterized by an uncontrolled proliferation of aberrant plasma cells in the bone marrow. Chromosome aberrations in MM are complex and represent a hallmark of the disease, involving many chromosomes that are altered both numerically and structurally. Nearly half of the cases are nonhyperdiploid and show IGH translocations with the following partner genes: CCND1, FGFR3 and MMSET, MAF, MAFB, and CCND3. The remaining 50% are grouped into a hyperdiploid group that is characterized by multiple trisomies involving chromosomes 3, 5, 7, 9, 11, 15, 19, and 21. In this study, we analyzed the immunoglobulin light chain kappa (IGK, 2p12) and lambda (IGL, 22q11) loci in 150 cases, mostly with MM but in a few cases monoclonal gammopathy of undetermined significance (MGUS), without IGH translocations. We identified aberrations in 27% (= 40 patients) including rearrangements (12%), gains (12%), and deletions (4.6%). In 6 of 18 patients with IGK or/and IGL rearrangements, we detected a MYC rearrangement which suggests that MYC is the translocation partner in the majority of these cases.

Related: FISH

Ahmad N, Haider S, Jagannathan S, et al.
MicroRNA theragnostics for the clinical management of multiple myeloma.
Leukemia. 2014; 28(4):732-8 [PubMed] Related Publications
Theragnostics represent cutting-edge, multi-disciplinary strategies that combine diagnostics with therapeutics in order to generate personalized therapies that improve patient outcome. In oncology, the approach is aimed at more accurate diagnosis of cancer, optimization of patient selection to identify those most likely to benefit from a specific therapy and to generate effective therapeutics that enhance patient survival. MicroRNAs (miRNAs) are master regulators of the human genome that orchestrate myriad cellular pathways to control growth during physiologic and pathologic conditions. Compelling evidence shows that miRNA deregulation promotes events linked to tumor initiation, metastasis and drug resistance as seen in multiple myeloma (MM), an invariably fatal hematologic malignancy. miRNAs are readily detected in body fluids, for example, serum, plasma, urine, as well as circulating tumor cells to demonstrate their potential as readily accessible, non-invasive diagnostic and prognostic biomarkers and potential therapeutics. Specific miRNAs are aberrantly expressed early in myelomagenesis and may more readily detect high-risk disease than current methods. Although only recently discovered miRNAs have rapidly advanced from preclinical studies to evaluation in human clinical trials. The development of miRNA theragnostics should provide widely applicable tools for the targeted delivery of personalized medicines to improve the outcome of patients with MM.

He L, Ji JN, Liu SQ, et al.
Expression of cancer-testis antigen in multiple myeloma.
J Huazhong Univ Sci Technolog Med Sci. 2014; 34(2):181-5 [PubMed] Related Publications
Recently, the immunotherapy has been highlighted among cancer treatments. Cancer-testis antigen (CTA) has been studied in a variety of solid tumors because of its specific expression in tumors, and testis, ovary and placenta tissues, but not in other normal tissues. In order to provide a new approach for multiple myeloma (MM) immunotherapy, we examined the CTA expression in MM cell lines, and primary myeloma cells in patients with MM. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to detect the mRNA expression of MAGE-C1/CT7, SSX1, SSX2 and SSX4 in MM cell lines of RPMI-8226 and U266, and bone marrow (BM) cells of 25 MM patients and 18 healthy volunteers. The results showed that the 4 CTAs were expressed in RPMI-8226 and U266 cell lines. The positive expression rate of MAGE-C1/CT7, SSX1, SSX2 and SSX4 in the BM cells of 25 MM patients was 28% (7/25), 80% (20/25), 40% (10/25) and 68% (17/25), respectively. In contrast, the expression of any member of the CTAs was not detected in BM cells of 18 healthy volunteers. The expression of two or more CTAs was detected in 80% (20/25) MM patients, and that of at least one CTA in 88% (22/25). The mRNA expression levels of SSX1 and SSX4 were significantly higher in patients with MM at stage III than in those at stage I and II (P<0.05). No statistically significant differences were observed in the mRNA expression levels of MAGE-C1/CT7 and SSX2 in further stratified analyses by age, gender, MM types and percentage of MM cells in BM (P>0.05). In conclusion, our present study showed that MAGE-C1/CT7, SSX1, SSX2 and SSX4 were co-expressed in MM cell lines and the primary myeloma cells in MM patients, but not expressed in BM cells of healthy subjects. The mRNA levels of SSX1 and SSX4 are associated with MM clinical stage. This work may provide a new insight into MM immunotherapy in the future.

Brito AB, Lourenço GJ, Oliveira GB, et al.
Associations of VEGF and VEGFR2 polymorphisms with increased risk and aggressiveness of multiple myeloma.
Ann Hematol. 2014; 93(8):1363-9 [PubMed] Related Publications
Angiogenesis has been highlighted as a critical component in the progression of multiple myeloma (MM), and vascular endothelial growth factor (VEGF) as well as its type 2 receptor (VEGFR2) are thought to play a major role in the process. Single nucleotide polymorphisms (SNPs) have been described in VEGF and VEGFR2 genes, with quantitative or qualitative changes in encoded VEGF and VEGFR2. The roles of VEGF -2578C/A, -1154G/A, and -634G/C as well as VEGFR2 -604T/C and +1192G/A SNPs in the risk and manifestations of MM are still unknown; therefore, this study aimed to clarify this issue. DNA from 192 patients and 209 controls were analyzed by real-time polymerase chain reaction for identification of genotypes. The frequencies of VEGF -2578CC, VEGF -2578CC plus VEGF -634GG, and VEGF -2578CC plus VEGF -1154GG plus VEGF -634GG genotypes were higher in patients than in controls. Carriers of the respective genotypes had a 1.89-, a 5.52-, and a 4.91-fold increased risk for MM than others. VEGF -2578CC plus VEGFR2 +1192GG, VEGF -2578CC plus VEGF -634GG plus VEGFR2 +1192GG, and VEGF -1154GG plus VEGF -634GG plus VEGFR2 -604TT combined genotypes were more common in patients than in controls. Carriers of the respective genotypes had a 2.56-, a 10.97-, and a 14.10-fold increased risk for MM than others. An excess of VEGFR2 -604TT genotype was also seen in patients with stage II or III tumors when compared with those with stage I tumors. Our data suggest, for the first time, that inherited abnormalities in VEGF and VEGFR2 pathways influence the risk and aggressiveness of MM.

Related: Angiogenesis and Cancer VEGFA

Oh S, Koo DH, Kwon MJ, et al.
Chromosome 13 deletion and hypodiploidy on conventional cytogenetics are robust prognostic factors in Korean multiple myeloma patients: web-based multicenter registry study.
Ann Hematol. 2014; 93(8):1353-61 [PubMed] Related Publications
This study was designed to evaluate the prevalence of chromosomal abnormalities and to identify the specific abnormalities associated with poor prognosis. A total of 2,474 patients whose conventional cytogenetics were available at the time of diagnosis were evaluated via a nationwide registry. Normal metaphase cytogenetics was observed in 2,012 patients (81.3%). Among the 462 patients with chromosomal abnormalities, there were 161 (34.8%) patients with hyperdiploidy, 197 (42.6%) with pseudodiploidy, 79 (17.1%) with hypodiploidy, and 25 (5.5%) with near-tetraploidy. Deletion 13 (Δ13) in metaphase was observed in 167 patients (6.8%). Fluorescent in situ hybridization (FISH) was carried out in 967 patients (39.1%), and 66 (13.7%) out of 482 and 63 (10.3%) out of 611 patients were positive for t(4;14) and del(17p), respectively. With a median follow-up duration of 25.1 months, the median overall survival (OS) was 51.2 months (95% confidence interval, 46.5-55.9 months). In univariate analysis, the following four chromosomal abnormalities were significantly associated with a poor survival outcome: Δ13, hypodiploidy, del(13q) in FISH, and del(17p) in FISH. In the subsequent multivariate analysis, in which del(13q) and del(17p) in FISH were excluded due to a relatively low number of patients, Δ13 and hypodiploid status were independently associated with a poor survival outcome after adjusting for important clinical factors, including age, sex, performance, beta2-microglobulin, albumin, and lactate dehydrogenase (LDH). Using conventional metaphase cytogenetics, we confirmed that both Δ13 and hypodiploid status were robust poor prognostic factors. The metaphase karyotyping should remain the primary cytogenetic tool and an essential investigation for risk stratification in newly diagnosed multiple myeloma patients.

Related: Chromosome 13 FISH

Martinez-Lopez J, Lahuerta JJ, Pepin F, et al.
Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma.
Blood. 2014; 123(20):3073-9 [PubMed] Article available free on PMC after 12/06/2015 Related Publications
We assessed the prognostic value of minimal residual disease (MRD) detection in multiple myeloma (MM) patients using a sequencing-based platform in bone marrow samples from 133 MM patients in at least very good partial response (VGPR) after front-line therapy. Deep sequencing was carried out in patients in whom a high-frequency myeloma clone was identified and MRD was assessed using the IGH-VDJH, IGH-DJH, and IGK assays. The results were contrasted with those of multiparametric flow cytometry (MFC) and allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The applicability of deep sequencing was 91%. Concordance between sequencing and MFC and ASO-PCR was 83% and 85%, respectively. Patients who were MRD(-) by sequencing had a significantly longer time to tumor progression (TTP) (median 80 vs 31 months; P < .0001) and overall survival (median not reached vs 81 months; P = .02), compared with patients who were MRD(+). When stratifying patients by different levels of MRD, the respective TTP medians were: MRD ≥10(-3) 27 months, MRD 10(-3) to 10(-5) 48 months, and MRD <10(-5) 80 months (P = .003 to .0001). Ninety-two percent of VGPR patients were MRD(+). In complete response patients, the TTP remained significantly longer for MRD(-) compared with MRD(+) patients (131 vs 35 months; P = .0009).

Tian E, Sawyer JR, Heuck CJ, et al.
In multiple myeloma, 14q32 translocations are nonrandom chromosomal fusions driving high expression levels of the respective partner genes.
Genes Chromosomes Cancer. 2014; 53(7):549-57 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
In studies of patients with multiple myeloma (MM), gene expression profiling (GEP) of myeloma cells demonstrates substantially higher expression of MMSET, FGFR3, CCND3, CCND1, MAF, and MAFB--the partner genes of 14q32 translocations--than GEP of plasma cells from healthy individuals. Interphase fluorescent in situ hybridization (FISH) was used to discriminate between chromosomal translocations involving different regions of the immunoglobulin heavy chain (IGH) genes at 14q32. With special probes designed for the constant region (IGHC) and the variable region (IGHV), IGH translocations were shown to be definite, nonrandom chromosomal fusions of IGHC with the loci of FGFR3, CCND1, CCND3, MAF, and MAFB genes; and IGHV with the locus of MMSET gene. When correlated with GEP results, the IGH translocations were found to drive expression levels of the partner genes to significantly higher levels (spikes) than copy-number variations. Hence, 42% of IGH translocations were identified among newly diagnosed MM patients (448/1,060). As GEP has become essential for assessing cancer risk, this novel approach is highly consistent with the cytogenetic features of the chromosomal translocations to effectively stratify molecular subgroups of MM on the basis of gene expression profiles of the IGH translocation partner genes in myeloma cells. © 2014 Wiley Periodicals, Inc.

Related: Chromosome 14

Vij R, Mazumder A, Klinger M, et al.
Deep sequencing reveals myeloma cells in peripheral blood in majority of multiple myeloma patients.
Clin Lymphoma Myeloma Leuk. 2014; 14(2):131-139.e1 [PubMed] Related Publications
INTRODUCTION: The evaluation of myeloma cells in multiple myeloma (MM) patients has generally been limited to the assessment of bone marrow involvement because of the sensitivity limitations of traditional minimal-residual-disease-detection methods.
MATERIALS AND METHODS: We developed a sequencing-based method to identify myeloma cells in bone marrow (BM) and peripheral blood (PB) samples, based on their unique immunoglobulin gene rearrangements, that can detect cancer clones at levels well below 1 in 1 million leukocytes (0.0001%). In this multisite study, we used this sequencing method to determine the fraction of patients with myeloma cells in their PB at diagnosis and posttreatment time points.
RESULTS: Using this sequencing approach, we detected myeloma cells in the PB in the vast majority of MM patients (44/46, 96%). We demonstrated a clear correlation (R(2) = 0.57) between myeloma clone levels in paired BM and PB samples, and noted that PB clone levels were approximately 100-fold lower than levels in BM samples. The sequencing assay demonstrated a clear sensitivity advantage in the BM compartment and at least equivalent sensitivity in the PB compared with that of monoclonal-protein results.
CONCLUSION: This study highlights the promise of a blood-based, sequencing minimal-residual-disease assay that can be used to measure MM disease burden at different time points and various disease stages.

Teoh PJ, Chung TH, Sebastian S, et al.
p53 haploinsufficiency and functional abnormalities in multiple myeloma.
Leukemia. 2014; 28(10):2066-74 [PubMed] Related Publications
Hemizygous deletion of 17p13, which harbors the TP53 gene, has been identified in >10% of newly diagnosed multiple myeloma (MM) patients and is associated with poor prognosis. To date, there is no conclusive evidence that TP53 is the critical gene. Furthermore, the functional effect of TP53 haploinsufficiency is not well characterized. By utilizing human myeloma cell lines, we showed that TP53 hemizygous loss was associated with decreased basal expression level with a partially or severely inactivated p53 response upon genotoxic and non-genotoxic stress. The pathway deficiency was manifested as defective p53 transcriptional activities, together with significant resistance to apoptosis. In some cases with p53 WT/- and no p53 protein expression, the remaining allele was silenced by promoter hypermethylation. We also developed a p53 target gene signature to summarize the complexity of the p53 pathway abnormalities in MM and showed that it is strongly associated with genomic complexity and patient survival. In conclusion, this study identified TP53 as the critical gene located in 17p13, and revealed its haploinsufficiency properties in MM. Furthermore, we have elucidated that multiple mechanisms can deregulate the p53 functions and that this has important prognostic impact in MM.

Related: Apoptosis Chromosome 17 CGH Signal Transduction TP53

Campo S, Allegra A, D'Ascola A, et al.
MiRNome expression is deregulated in the peripheral lymphoid compartment of multiple myeloma.
Br J Haematol. 2014; 165(6):801-13 [PubMed] Related Publications
MicroRNAs (miRNAs) are short non-coding RNAs involved in the regulation of gene expression. Selected groups of miRNAs are differentially expressed in various types of cancers. Alterations in miRNAs gene expression have been shown in cells from the B-cell malignancy, multiple myeloma (MM). However, although MM is a disease of plasma cells, abnormalities have been detected in the peripheral blood of the patients. The goal of our study was to analyse the entire miRNome in peripheral lymphocytes of MM patients using reverse transcription quantitative polymerase chain reaction. Using in silica analysis, we also evaluated some of the most interesting and significant pathways. Analysis revealed that MM samples had a distinct miRNA profile compared to the controls. This resulted in the identification of 203 miRNAs, 85 of which were over-expressed and 118 under-expressed. Of these, 184 possessed validated or highly predicted mRNA targets. We identified 12 354 mRNA targets of the transcriptome: 36·4% of the related proteins are involved in death processes while the 21% are required for growth and cell proliferation. We have demonstrated that miRNAs are differentially expressed in the peripheral blood of MM patients compared to controls, affecting some pathways involved in the anti-apoptotic process, cell proliferation and maybe anti-angiogenesis.

Related: Signal Transduction

Biran N, Malhotra J, Bagiella E, et al.
Patients with newly diagnosed multiple myeloma and chromosome 1 amplification have poor outcomes despite the use of novel triplet regimens.
Am J Hematol. 2014; 89(6):616-20 [PubMed] Related Publications
The prognostic impact of amplification of chromosome 1(C1A) in newly diagnosed multiple myeloma (nMM) patients treated with the most commonly used bortezomib-based triplet regimens is unclear. In this study, we analyzed the outcome of novel triplet therapies in a series of unselected patients with C1A detected by FISH. We identified 28 unselected nMM patients with C1A who had a gain of 1q21 locus. Despite 50% of patients being diagnosed at ISS stage 1 or 2 and 93% having no other high-risk molecular findings, the median overall survival of all patients was only 37 months, with 8 deaths (29%) occurring 8-37 months after diagnosis. Those who died had a median of four lines (range was 1-8) of therapy. Moreover, 71% of patients were non-Caucasian. Extra-osseous and CNS involvement occurred in 36 and 11% of patients respectively. Gain of the long arm of chromosome 1 detected by FISH remains a high-risk prognostic marker even in the setting of novel triplet therapies.

Related: Chromosome 1 FISH

Zhao JJ, Lin J, Zhu D, et al.
miR-30-5p functions as a tumor suppressor and novel therapeutic tool by targeting the oncogenic Wnt/β-catenin/BCL9 pathway.
Cancer Res. 2014; 74(6):1801-13 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
Wnt/β-catenin signaling underlies the pathogenesis of a broad range of human cancers, including the deadly plasma cell cancer multiple myeloma. In this study, we report that downregulation of the tumor suppressor microRNA miR-30-5p is a frequent pathogenetic event in multiple myeloma. Evidence was developed that miR-30-5p downregulation occurs as a result of interaction between multiple myeloma cells and bone marrow stromal cells, which in turn enhances expression of BCL9, a transcriptional coactivator of the Wnt signaling pathway known to promote multiple myeloma cell proliferation, survival, migration, drug resistance, and formation of multiple myeloma cancer stem cells. The potential for clinical translation of strategies to re-express miR-30-5p as a therapeutic approach was further encouraged by the capacity of miR-30c and miR-30 mix to reduce tumor burden and metastatic potential in vivo in three murine xenograft models of human multiple myeloma without adversely affecting associated bone disease. Together, our findings offer a preclinical rationale to explore miR-30-5p delivery as an effective therapeutic strategy to eradicate multiple myeloma cells in vivo.

Related: Apoptosis BCL9 gene

Zhang L, Zhou L, Du J, et al.
Induction of apoptosis in human multiple myeloma cell lines by ebselen via enhancing the endogenous reactive oxygen species production.
Biomed Res Int. 2014; 2014:696107 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
Ebselen a selenoorganic compound showing glutathione peroxidase like activity is an anti-inflammatory and antioxidative agent. Its cytoprotective activity has been investigated in recent years. However, experimental evidence also shows that ebselen causes cell death in several cancer cell types whose mechanism has not yet been elucidated. In this study, we examined the effect of ebselen on multiple myeloma (MM) cell lines in vitro. The results showed that ebselen significantly enhanced the production of reactive oxygen species (ROS) accompanied by cell viability decrease and apoptosis rate increase. Further studies revealed that ebselen can induce Bax redistribution from the cytosol to mitochondria leading to mitochondrial membrane potential ΔΨm changes and cytochrome C release from the mitochondria to cytosol. Furtherly, we found that exogenous addition of N-acetyl cysteine (NAC) completely diminished the cell damage induced by ebselen. This result suggests that relatively high concentration of ebselen can induce MM cells apoptosis in culture by enhancing the production of endogenous ROS and triggering mitochondria mediated apoptotic pathway.

Related: Apoptosis Signal Transduction

Di Martino MT, Campani V, Misso G, et al.
In vivo activity of miR-34a mimics delivered by stable nucleic acid lipid particles (SNALPs) against multiple myeloma.
PLoS One. 2014; 9(2):e90005 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
Multiple myeloma (MM) is a disease with an adverse outcome and new therapeutic strategies are urgently awaited. A rising body of evidence supports the notion that microRNAs (miRNAs), master regulators of eukaryotic gene expression, may exert anti-MM activity. Here, we evaluated the activity of synthetic miR-34a in MM cells. We found that transfection of miR-34a mimics in MM cells induces a significant change of gene expression with relevant effects on multiple signal transduction pathways. We detected early inactivation of pro-survival and proliferative kinases Erk-2 and Akt followed at later time points by caspase-6 and -3 activation and apoptosis induction. To improve the in vivo delivery, we encapsulated miR-34a mimics in stable nucleic acid lipid particles (SNALPs). We found that SNALPs miR-34a were highly efficient in vitro in inhibiting growth of MM cells. Then, we investigated the activity of the SNALPs miR-34a against MM xenografts in SCID mice. We observed significant tumor growth inhibition (p<0.05) which translated in mice survival benefits (p=0.0047). Analysis of miR-34a and NOTCH1 expression in tumor retrieved from animal demonstrated efficient delivery and gene modulation induced by SNALPs miR-34a in the absence of systemic toxicity. We here therefore provide evidence that SNALPs miR-34a may represent a promising tool for miRNA-therapeutics in MM.

Related: Apoptosis AKT1 Signal Transduction

Recurrent Structural Abnormalities

Selected list of common recurrent structural abnormalities

Abnormality Type Gene(s)
Loss of Chromosome 13 in MyelomaDeletion
t(11;14)(q13;q32) in MyelomaTranslocation
t(6;14)(p25;q32) in MyelomaTranslocationIRF4 (6p25-p23)IGH (14q32.33)
Occasional translocation of MAFB in MyelomaTranslocationMAFB (20q11.2-q13.1)

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

Loss of Chromosome 13 in Myeloma

Avet-Loiseau H, Li JY, Morineau N, et al.
Monosomy 13 is associated with the transition of monoclonal gammopathy of undetermined significance to multiple myeloma. Intergroupe Francophone du Myélome.
Blood. 1999; 94(8):2583-9 [PubMed] Related Publications
Chromosomal abnormalities are present in most (if not all) patients with multiple myeloma (MM) and primary plasma cell leukemia (PCL). Furthermore, recent data have shown that numerical chromosomal changes are present in most individuals with monoclonal gammopathy of undetermined significance (MGUS). Epidemiological studies have shown that up to one third of MM may emerge from pre-existing MGUS. To clarify further possible stepwise chromosomal aberrations on a pathway between MGUS and MM, we have analyzed 158 patients with either MM or primary PCL and 19 individuals with MGUS using fluorescence in situ hybridization (FISH). Our FISH analyses were designed to detect illegitimate IGH rearrangements at 14q32 or monosomy 13. Whereas translocations involving the 14q32 region were observed with a similar incidence (60%) in both conditions, a significant difference was found in the incidence of monosomy 13 in MGUS versus MM or primary PCL. It was present in 40% of MM/PCL patients, but in only 4 of 19 MGUS individuals. Moreover, whereas monosomy 13 was found in the majority of plasma cells in MM, it was observed only in cell subpopulations in MGUS. It is noteworthy that, in a group of 20 patients with MM and a previous MGUS history, incidence of monosomy 13 was 70% versus 31% in MM patients without a known history of MGUS (P =.002). Thus, this study highlights monosomy 13 as correlated with the transformation of MGUS to overt MM and may define 2 groups of MM with possible different natural history and outcome, ie, post-MGUS MM with a very high incidence of monosomy 13 and de novo MM in which other genetic events might be involved. Serial analyses of individuals with MGUS will be needed to validate this model.

Related: Chromosome 13 Chromosome 14 FISH

Zojer N, Königsberg R, Ackermann J, et al.
Deletion of 13q14 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization.
Blood. 2000; 95(6):1925-30 [PubMed] Related Publications
Interphase fluorescence in situ hybridization (FISH) studies of chromosomal region 13q14 were performed to investigate the incidence and clinical importance of deletions in multiple myeloma (MM). Monoallelic deletions of the retinoblastoma-1 (rb-1) gene and the D13S319 locus were observed in 48 of 104 patients (46.2%) and in 28 of 72 (38.9%) patients, respectively, with newly diagnosed MM. FISH studies found that 13q14 was deleted in all 17 patients with karyotypic evidence of monosomy 13 or deletion of 13q but also in 9 of 19 patients with apparently normal karyotypes. Patients with a 13q14 deletion were more likely to have stage III disease (P =.022), higher serum levels of beta(2)-microglobulin (P =.059), and a higher percentage of bone marrow plasma cells (P =.085) than patients with a normal 13q14 status on FISH analysis. In patients with a deletion of 13q14, myeloma cell proliferation (Ki-67) was markedly increased (22.0% +/- 6.9% compared with 15.6% +/- 8.2% in patients without the deletion; P =.0008). Evaluation of bromodeoxyuridine incorporation in 5 patients revealed that both rb-1-deleted and rb-1-normal MM subpopulations were proliferative. The presence of a 13q14 deletion on FISH analysis was associated with a significantly lower rate of response to conventional-dose chemotherapy (40.8% compared with 78. 6%; P =.009) and a shorter overall survival (24.2 months compared with > 60 months; P <.005) than in patients without the deletion. Multivariate analysis of prognostic factors confirmed the independent predictive value of 13q14 deletions for shortened survival. In conclusion, deletions of 13q14 are frequently detected by interphase FISH in patients with newly diagnosed MM, correlate with increased proliferative activity, and represent an independent adverse prognostic feature in MM. (Blood. 2000;95:1925-1930)

Related: Chromosome 13 FISH RB1

t(11;14)(q13;q32) in Myeloma

t(11;14)(q13;q32) is the most common chromosome translocation in multiple myeloma (An et al, 2013).

An G, Xu Y, Shi L, et al.
t(11;14) multiple myeloma: a subtype associated with distinct immunological features, immunophenotypic characteristics but divergent outcome.
Leuk Res. 2013; 37(10):1251-7 [PubMed] Related Publications
UNLABELLED: t(11;14)(q13;q32) is the most common chromosome translocation in multiple myeloma (MM), but a consensus of clinicopathological features and impact on survival is yet to be reached. We analyzed a cohort of 350 patients with various plasma cell malignancies, including newly diagnosed MM (NDMM, n=253), relapsed/refractory MM (RRMM, n=77), as well as primary and secondary plasma cell leukemia (PCL, n=10 and n=10, respectively).
RESULTS: A remarkably higher frequency of t(11;14) was observed in the PCL than in the NDMM. A high incidence of t(11;14) was detected in the IgD, IgM, and nonsecretory MM. The t(11;14) MM group was associated with a significantly higher positive rate of B-lineage associated antigens CD20 and CD79a as well as the lack of CD56 expression. t(11;14) was less likely to be accompanied by 13q14 deletion than 13q14 deletion frequency in non-t(11;14) population (p=0.026), and fewer patients displaying t(11;14) were identified as belonging to the high-risk cytogenetic group due to the extremely low incidence of t(4;14) and t(14;16). As a whole, patients exhibiting t(11;14) had a comparable outcome with the control cohort in NDMM, but CD20 was able to identify two subsets of the disease with dissimilar outcomes. Among patients receiving bortezomib-based treatment, patients harboring t(11;14) without CD20 expression had a significantly shortened PFS (11.0 versus 43.0 months, p=0.005) and OS (16.5 versus 54.0 months, p=0.016) compared with patients displaying t(11;14) with CD20. Our findings suggest that although the t(11;14) plasma cell disorder displayed distinct biological, clinical and laboratory features, it was a heterogeneous disease with divergent outcome.

Related: Chromosome 11 Chromosome 14

Avet-Loiseau H, Facon T, Daviet A, et al.
14q32 translocations and monosomy 13 observed in monoclonal gammopathy of undetermined significance delineate a multistep process for the oncogenesis of multiple myeloma. Intergroupe Francophone du Myélome.
Cancer Res. 1999; 59(18):4546-50 [PubMed] Related Publications
Clonal plasma cells in monoclonal gammopathy of undetermined significance (MGUS) have been shown to bear copy number chromosome changes. To extend our knowledge of MGUS to structural chromosomal abnormalities, we have performed fluorescence in situ hybridization experiments with probes directed to the 14q32 and 13q14 chromosomal regions in 100 patients with either MGUS or smoldering multiple myeloma (SMM). 14q32 abnormalities were observed in at least 46% of patients with MGUS/SMM, with these abnormalities being present in the majority of clonal plasma cells. Whereas t(11;14)(q13;q32) occurs in 15% of MGUS/SMM patients, an incidence similar to that of overt multiple myeloma (MM) patients, translocation t(4;14)(p16;q32) is observed in only 2% of these cases [P = 0.002 for difference with t(11;14)], as compared with 12% in MM patients (P = 0.013). Monoallelic deletions of the 13q14 region were found in 21% of patients, with two types of situations. In half of the evaluable patients, and especially in patients with SMM, the deletion is present in the majority of clonal plasma cells, as in MM, whereas in the other half of the evaluable patients (essentially in MGUS patients), it is observed in subclones only. These data enable us to elaborate a plasma cell oncogenesis model from MGUS to MM.

Related: Chromosome 11 Chromosome 13 Chromosome 14 Chromosome 4

Janssen JW, Vaandrager JW, Heuser T, et al.
Concurrent activation of a novel putative transforming gene, myeov, and cyclin D1 in a subset of multiple myeloma cell lines with t(11;14)(q13;q32).
Blood. 2000; 95(8):2691-8 [PubMed] Related Publications
Through the application of the NIH/3T3 tumorigenicity assay to DNA from a gastric carcinoma, we have identified a novel transforming gene, designated myeov (myeloma overexpressed gene in a subset of t[11;14]-positive multiple myelomas). Sequence analyses did not reveal any homology with sequences present in the GenBank, except the deduced protein structure predicts a transmembrane localization. Myeov was mapped to chromosome 11q13 and localized by DNA fiber fluorescence in situ hybridization (FISH) 360-kilobase (kb) centromeric of cyclin D1. In 3 of 7 multiple myeloma (MM) cell lines with a t(11;14)(q13;q32) and cyclin-D1 overexpression, Northern blot analysis revealed overexpression of myeov as well. In all 7 cell lines, the translocation breakpoint was mapped within the 360-kb region between myeov and cyclin D1. DNA fiber FISH with a contig of probes covering the constant region of the immunoglobulin heavy chain (IgH) revealed that exclusively in the 3 myeov-overexpressing cell lines (KMS-12, KMS-21, and XG-5), either the 5' E(mu) enhancer or the most telomeric 3' Ealpha enhancer was juxtaposed to myeov. Although cyclin D1 overexpression represents a characteristic feature of all MM cell lines with t(11;14), our results demonstrate aberrant expression of a second putative oncogene in a subset of these cases, due to juxtaposition to IgH enhancers. The clinical relevance of this dual activation remains to be elucidated. (Blood. 2000;95:2691-2698)

Related: Chromosome 11 Chromosome 14

Hoyer JD, Hanson CA, Fonseca R, et al.
The (11;14)(q13;q32) translocation in multiple myeloma. A morphologic and immunohistochemical study.
Am J Clin Pathol. 2000; 113(6):831-7 [PubMed] Related Publications
We identified 24 cases of multiple myeloma with the t(11;14)(q13;q32). In 22 cases, the t(11;14)(q13;q32) was part of a complex karyotype, and in 2 cases it was an isolated abnormality. All patients had clinical and laboratory features consistent with multiple myeloma. The median degree of plasma cell involvement in the bone marrow was 60%, and in 10 cases, the plasma cells had a lymphoplasmacytoid appearance. Of the 24 cases, 21 had intermediate or high proliferative rates based on labeling index studies. Immunohistochemical studies performed on all bone marrow biopsy specimens showed strong cyclin D1 nuclear positivity in 19 cases. There also was strong cyclin D1 nuclear positivity found in 6 of 30 additional cases without the t(11;14)(q13;q32) demonstrated by routine cytogenetics. The t(11;14)(q13;q32) in multiple myeloma results in overexpression of the cyclin D1 protein, which can be demonstrated by immunohistochemical stain. The cyclin D1 stain results in the additional cases of multiple myeloma suggest that the t(11;14)(q13;q32) may be more common than previously thought and may be missed by routine cytogenetics, particularly if the proliferative rate is low.

Related: Chromosome 11 Chromosome 14


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