Myeloma - Molecular Biology

Overview

Literature Analysis

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

  • SDC1
  • Antineoplastic Agents
  • Chromosome Aberrations
  • Multiple Myeloma
  • Case-Control Studies
  • Cancer RNA
  • Cell Proliferation
  • Proto-Oncogene Proteins c-myc
  • Drug Resistance
  • Survival Rate
  • Gene Expression
  • drug, Bortezomib (Velcade)
  • TNFRSF11B
  • Tumor Burden
  • Monoclonal Gammopathy of Undetermined Significance
  • RT-PCR
  • Disease Progression
  • Gene Expression Profiling
  • DKK1
  • Urokinase-Type Plasminogen Activator
  • Receptors, Somatomedin
  • Reproducibility of Results
  • Disease-Free Survival
  • Transcription Factors
  • Bone Marrow
  • CIC
  • Receptor, Fibroblast Growth Factor, Type 3
  • Cell Survival
  • Biomarkers, Tumor
  • CCND2
  • Staging
  • Transcriptome
  • Apoptosis
  • Chromosome 14
  • Genetic Predisposition
  • MAF
  • NFKB1
  • MicroRNAs
  • Proportional Hazards Models
  • DNA Methylation
  • FISH
  • Messenger RNA
  • Precursor Cells, B-Lymphoid
  • Mutation
  • BIRC3
  • P-Glycoprotein
  • Cancer Gene Expression Regulation
Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (84)

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'.

GeneLocationAliasesNotesTopicPapers
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
268
TNFRSF11B 8q24 OPG, TR1, OCIF -TNFRSF11B and Multiple Myeloma
124
FGFR3 4p16.3 ACH, CEK2, JTK4, CD333, HSFGFR3EX -FGFR3 and Multiple Myeloma
124
TNFRSF11A 18q22.1 FEO, OFE, ODFR, OSTS, PDB2, RANK, CD265, OPTB7, TRANCER, LOH18CR1 -TNFRSF11A and Multiple Myeloma
64
MAF 16q22-q23 CCA4, AYGRP, c-MAF, CTRCT21 -MAF and Multiple Myeloma
64
CD19 16p11.2 B4, CVID3 -CD19 and Multiple Myeloma
61
SDC1 2p24.1 SDC, CD138, SYND1, syndecan -SDC1 and Multiple Myeloma
37
WHSC1 4p16.3 WHS, NSD2, TRX5, MMSET, REIIBP -WHSC1 and Multiple Myeloma
31
DKK1 10q11.2 SK, DKK-1 -DKK1 and Multiple Myeloma
23
IFNA7 9p22 IFNA-J, IFN-alphaJ -IFNA7 and Multiple Myeloma
20
IFNA17 9p22 IFNA, INFA, LEIF2C1, IFN-alphaI -IFNA17 and Multiple Myeloma
20
CCND2 12p13 MPPH3, KIAK0002 -CCND2 and Multiple Myeloma
20
IFNA2 9p22 IFNA, INFA2, IFNA2B, IFN-alphaA -IFNA2 and Multiple Myeloma
20
TNFSF11 13q14 ODF, OPGL, sOdf, CD254, OPTB2, RANKL, TRANCE, hRANKL2 -TNFSF11 and Multiple Myeloma
18
CCND3 6p21 -CCND3 and Multiple Myeloma
16
IGL 22q11.2 IGL@, IGLC6 -IGL and Multiple Myeloma
15
CKS1B 1q21.2 CKS1, ckshs1, PNAS-16, PNAS-18 -CKS1B and Multiple Myeloma
14
CCL3 17q12 MIP1A, SCYA3, G0S19-1, LD78ALPHA, MIP-1-alpha -CCL3 and Multiple Myeloma
13
NFKB1 4q24 p50, KBF1, p105, EBP-1, NF-kB1, NFKB-p50, NFkappaB, NF-kappaB, NFKB-p105, NF-kappa-B -NFKB1 and Multiple Myeloma
13
IGK 2p12 IGK@ -IGK and Multiple Myeloma
12
PRDM1 6q21 BLIMP1, PRDI-BF1 -PRDM1 and Multiple Myeloma
12
IRF4 6p25-p23 MUM1, LSIRF, SHEP8, NF-EM5 Translocation
-t(6;14)(p25;q32) in Myeloma
11
CIC 19q13.2 -CIC and Multiple Myeloma
11
TRAF3 14q32.32 CAP1, LAP1, CAP-1, CRAF1, IIAE5, CD40bp -TRAF3 and Multiple Myeloma
11
TNFRSF17 16p13.1 BCM, BCMA, CD269, TNFRSF13A -TNFRSF17 and Multiple Myeloma
10
XBP1 22q12.1 XBP2, TREB5, XBP-1, TREB-5 -XBP1 and Multiple Myeloma
10
CD27 12p13 T14, S152, Tp55, TNFRSF7, S152. LPFS2 -CD27 and Multiple Myeloma
10
MUM1 19p13.3 MUM-1, EXPAND1, HSPC211 -MUM1 and Multiple Myeloma
9
B2M 15q21.1 -B2M and Multiple Myeloma
9
THRA 17q11.2 AR7, EAR7, ERBA, CHNG6, ERBA1, NR1A1, THRA1, THRA2, ERB-T-1, c-ERBA-1 -THRA and Multiple Myeloma
8
NFKB2 10q24 p52, p100, H2TF1, LYT10, CVID10, LYT-10, NF-kB2 -NFKB2 and Multiple Myeloma
8
IL6ST 5q11.2 CD130, GP130, CDW130, IL-6RB -IL6ST and Multiple Myeloma
7
BIRC3 11q22.2 AIP1, API2, MIHC, CIAP2, HAIP1, HIAP1, MALT2, RNF49, c-IAP2 -BIRC3 and Multiple Myeloma
6
FRZB 2q32.1 FRE, OS1, FZRB, hFIZ, FRITZ, FRP-3, FRZB1, SFRP3, SRFP3, FRZB-1, FRZB-PEN -FRZB and Multiple Myeloma
6
CCL4 17q12 ACT2, G-26, HC21, LAG1, LAG-1, MIP1B, SCYA2, SCYA4, MIP1B1, AT744.1, MIP-1-beta -CCL4 and Multiple Myeloma
6
TNFSF13B 13q32-q34 DTL, BAFF, BLYS, CD257, TALL1, THANK, ZTNF4, TALL-1, TNFSF20 -TNFSF13B and Multiple Myeloma
6
SCFV 14 -SCFV and Multiple Myeloma
6
GALM 2p22.1 GLAT, IBD1, BLOCK25, HEL-S-63p -GALM and Multiple Myeloma
5
CDR2 16p12.3 Yo, CDR62 -CDR2 and Multiple Myeloma
5
CYP2C8 10q23.33 CPC8, CYPIIC8, MP-12/MP-20 -CYP2C8 and Multiple Myeloma
5
ITGA4 2q31.3 IA4, CD49D -ITGA4 and Multiple Myeloma
5
FAM46C 1p12 -FAM46C and Multiple Myeloma
5
CD81 11p15.5 S5.7, CVID6, TAPA1, TSPAN28 -CD81 and Multiple Myeloma
4
HAS1 19q13.4 HAS -HAS1 and Multiple Myeloma
4
FAS 10q24.1 APT1, CD95, FAS1, APO-1, FASTM, ALPS1A, TNFRSF6 -FAS and Multiple Myeloma
4
TACC3 4p16.3 ERIC1, ERIC-1 -TACC3 and Multiple Myeloma
4
CD52 1p36 CDW52 -CD52 and Multiple Myeloma
4
MBL2 10q11.2 MBL, MBP, MBP1, MBPD, MBL2D, MBP-C, COLEC1, HSMBPC -MBL2 and Multiple Myeloma
4
BCL9 1q21 LGS -BCL9 and Multiple Myeloma
4
BIRC2 11q22.2 API1, MIHB, HIAP2, RNF48, cIAP1, Hiap-2, c-IAP1 -BIRC2 and Multiple Myeloma
4
CD58 1p13 ag3, LFA3, LFA-3 -CD58 and Multiple Myeloma
4
MERTK 2q14.1 MER, RP38, c-Eyk, c-mer, Tyro12 -MERTK and Multiple Myeloma
3
NR3C1 5q31.3 GR, GCR, GRL, GCCR, GCRST -NR3C1 and Multiple Myeloma
3
CD200 3q13.2 MRC, MOX1, MOX2, OX-2 -CD200 and Multiple Myeloma
3
ITGAL 16p11.2 CD11A, LFA-1, LFA1A -ITGAL and Multiple Myeloma
3
P2RX7 12q24 P2X7 -P2RX7 and Multiple Myeloma
3
IL6R 1q21 IL6Q, gp80, CD126, IL6RA, IL6RQ, IL-6RA, IL-6R-1 -IL6R and Multiple Myeloma
3
JAG2 14q32 HJ2, SER2 -JAG2 and Multiple Myeloma
3
TLR1 4p14 TIL, CD281, rsc786, TIL. LPRS5 -TLR1 and Multiple Myeloma
3
FCGR2A 1q23 CD32, FCG2, FcGR, CD32A, CDw32, FCGR2, IGFR2, FCGR2A1 -FCGR2A and Multiple Myeloma
3
SLC7A5 16q24.3 E16, CD98, LAT1, 4F2LC, MPE16, hLAT1, D16S469E -SLC7A5 and Multiple Myeloma
3
PIAS3 1q21 ZMIZ5 -PIAS3 and Multiple Myeloma
2
BAGE 21p11.1 not on ref BAGE1, CT2.1 -BAGE and Multiple Myeloma
2
HAS3 16q22.1 -HAS3 and Multiple Myeloma
2
IL21 4q26-q27 Za11, IL-21, CVID11 -IL21 and Multiple Myeloma
2
TLR7 Xp22.3 TLR7-like -TLR7 and Multiple Myeloma
2
PCDH10 4q28.3 PCDH19, OL-PCDH -PCDH10 and Multiple Myeloma
2
NFATC1 18q23 NFAT2, NFATc, NF-ATC, NF-ATc1.2 -NFATC1 and Multiple Myeloma
2
TYRO3 15q15 BYK, Dtk, RSE, Rek, Sky, Tif, Etk-2 -TYRO3 and Multiple Myeloma
2
PDCD5 19q13.11 TFAR19 -PDCD5 and Multiple Myeloma
2
POU2AF1 11q23.1 BOB1, OBF1, OCAB, OBF-1 -POU2AF1 and Multiple Myeloma
2
BACH2 6q15 BTBD25 -BACH2 and Multiple Myeloma
2
TNFSF13 17p13.1 APRIL, CD256, TALL2, ZTNF2, TALL-2, TRDL-1, UNQ383/PRO715 -TNFSF13 and Multiple Myeloma
2
ADAMTS9 3p14.1 -ADAMTS9 and Multiple Myeloma
1
RNF217-AS1 6q22.33 STL -STL and Multiple Myeloma
1
KL 13q12 -KL and Multiple Myeloma
1
CD47 3q13.1-q13.2 IAP, OA3, MER6 -CD47 and Multiple Myeloma
1
SLAMF1 1q23.3 SLAM, CD150, CDw150 -SLAMF1 and Multiple Myeloma
1
CD1D 1q23.1 R3, CD1A -CD1D and Multiple Myeloma
1
TRIM13 13q14 CAR, LEU5, RFP2, DLEU5, RNF77 -TRIM13 and Multiple Myeloma
1
SRPX Xp21.1 DRS, ETX1, SRPX1, HEL-S-83p -SRPX and Multiple Myeloma
1
ZNF331 19q13.42 RITA, ZNF361, ZNF463 -ZNF331 and Multiple Myeloma
1
MIR106B 7q22.1 MIRN106B, mir-106b -MIR106B and Multiple Myeloma
1
MAFB 20q12 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

Xu X, Liu J, Shen C, et al.
The role of ubiquitin-specific protease 14 (USP14) in cell adhesion-mediated drug resistance (CAM-DR) of multiple myeloma cells.
Eur J Haematol. 2017; 98(1):4-12 [PubMed] Related Publications
OBJECTIVE: Cell adhesion-mediated drug resistance (CAM-DR) is one of the mechanisms underlying the drug resistance in multiple myeloma (MM). Ubiquitin-specific protease 14 (USP14) is downregulated in the apoptotic model and upregulated in the adhesive model of MM. This study was undertaken to determine the role of USP14 in CAM-DR of MM cells.
METHODS: We examined the expression of USP14 in the apoptotic model of MM. The mechanism of USP14 in the process of apoptosis was further explored by flow cytometry assay and co-immunoprecipitation. We then performed the cell co-culture and adhesion assay and cell viability assay to investigate the effect of USP14 on adhesive rate and drug resistance in MM.
RESULTS: We discovered that USP14 played a negative role in cell apoptosis, which is correlated with Bcl-xl. Moreover, overexpression of USP14 in MM cell adhesion model could enhance the ability of cell adhesion by regulating Wnt-signaling pathways, thereby promoting the CAM-DR in MM.
CONCLUSION: USP14 participates in CAM-DR of MM through acting as a bridge between Bcl-xl apoptotic pathway and Wnt-signaling pathways and may be represented as a good candidate for pursuing clinical trials in MM.

Bong IP, Ng CC, Fakiruddin SK, et al.
Small interfering RNA-mediated silencing of nicotinamide phosphoribosyltransferase (NAMPT) and lysosomal trafficking regulator (LYST) induce growth inhibition and apoptosis in human multiple myeloma cells: A preliminary study.
Bosn J Basic Med Sci. 2016; 16(4):268-275 [PubMed] Free Access to Full Article Related Publications
Multiple myeloma (MM) is a malignancy of B lymphocytes or plasma cells. Our array-based comparative genomic hybridization findings revealed chromosomal gains at 7q22.3 and 1q42.3, where nicotinamide (NAM) phosphoribosyltransferase (NAMPT) and lysosomal trafficking regulator (LYST) genes are localized, respectively. This led us to further study the functions of these genes in myeloma cells. NAMPT is a key enzyme involved in nicotinamide adenine dinucleotide salvage pathway, and it is frequently overexpressed in human cancers. In contrast, little is known about the function of LYST in cancer. The expression of LYST is shown to affect lysosomal size, granule size, and autophagy in human cells. In this study, the effects of small interfering RNA (siRNA)-mediated silencing of NAMPT and LYST on cell proliferation and apoptosis were evaluated in RPMI 8226 myeloma cells. Transfection efficiencies were determined by quantitative real time reverse transcriptase PCR. Cell proliferation was determined using MTT assay, while apoptosis was analyzed with flow cytometry using Annexin V-fluorescein isothiocyanate/propidium iodide assay. The NAMPT protein expression in siRNA-treated cells was estimated by enzyme-linked immunosorbent assay. Our results showed that NAMPT and LYST were successfully knockdown by siRNA transfection (p < 0.05). NAMPT or LYST gene silencing significantly inhibited cell proliferation and induced apoptosis in RPMI 8226 cells (p < 0.05). Silencing of NAMPT gene also decreased NAMPT protein levels (p < 0.01). Our study demonstrated that NAMPT and LYST play pivotal roles in the molecular pathogenesis of MM. This is the first report describing the possible functions of LYST in myelomagenesis and its potential role as a therapeutic target in MM.

Li Y, Du Z, Wang X, et al.
Association of IL-6 Promoter and Receptor Polymorphisms with Multiple Myeloma Risk: A Systematic Review and Meta-Analysis.
Genet Test Mol Biomarkers. 2016; 20(10):587-596 [PubMed] Related Publications
BACKGROUND: A number of studies show that the pleiotropic cytokine interleukin-6 (IL-6) plays an important role in the pathogenesis of multiple myeloma (MM). However, whether MM risk is associated with IL-6 genetic variability remains uncertain.
OBJECTIVE: The aim of our study was to evaluate the association between two different IL-6 polymorphisms (located in the IL-6 promoter and receptor, respectively) and the risk of developing MM using a meta-analytic approach.
MATERIALS AND METHODS: A systematic search for studies on the association of IL-6/IL-6R single-nucleotide polymorphisms with susceptibility to MM was conducted in PubMed, Cochrane Library, Embase, CNKI (Chinese) and Wanfang (Chinese) Digital Dissertations Databases from inception through November 2014. A meta-analysis was performed and results were presented as odds ratios (ORs) with 95% confidence intervals (CIs).
RESULTS: A total of eight case-control studies on the IL-6 promoter polymorphism and three studies on the IL-6 receptor (IL-6R) polymorphism were included. No significant association was found between the IL-6 promoter rs1800795 (G>C) polymorphism and MM susceptibility. A significantly increased risk of MM was observed with the IL-6R rs8192284 (A>C) polymorphism. In subgroup analyses, grouped by ethnicity, region, quality of studies, and Hardy-Weinberg equilibrium of control group, similar results were found.
CONCLUSION: Unlike the IL-6 promoter rs1800795 (G>C) polymorphism, the IL-6R rs8192284 (A>C) polymorphism may be associated with MM risk. However, large-scale studies are needed to validate our findings since they are based on a relatively small number of studies.

Cen L, Jiang Y, Zhang X, et al.
[Correlation of cytogenetic changes with VEGF and TRacp-5b levels among 60 elderly patients with multiple myeloma].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2016; 33(5):602-5 [PubMed] Related Publications
OBJECTIVE: To assess the correlation of cytogenetic changes with serum vascular endothelial growth factor (VEGF) and serum tartrate resistant acid phosphatase (TRacp-5b) levels among elderly patients with multiple myeloma (MM).
METHODS: Chromosomal changes were analyzed with a modified culturing method in the presence of IL-6. Serum levels of VEGF and TRacp-5b were determined with enzyme-linked immunosorbent assays (ELISA).
RESULTS: Among the 60 MM patients, chromosomal abnormalities were found in 27 cases, including 22 with numerical abnormalities and 15 with structural abnormalities. Many patients had both numerical and structural abnormalities. For 33 patients with a normal karyotype, the levels of VEGF and TRacp-5b were 117.35 ± 55.26 pg/mL and 4.15 ± 2.15 U/L, respectively, while for 27 patients with an abnormal karyotype, the levels of VEGF and TRacp-5b were 190.26 ± 85.74 pg/ml and 5.96 ± 2.24 U/L, respectively. The difference between the two groups was significant (P<0.05).
CONCLUSION: Compared with MM patients with a normal karyotype, the levels of VEGF and TRacp-5b are higher in those with cytogenetic abnormalities.

Dai Z, Feng C, Zhang W, et al.
Lack of association between cytotoxic T-lymphocyte antigen-4 gene polymorphisms and lymphoid malignancy risk: evidence from a meta-analysis.
Ann Hematol. 2016; 95(10):1685-94 [PubMed] Related Publications
Cytotoxic T-lymphocyte antigen-4 (CTLA-4) polymorphisms have been associated with susceptibility to lymphoid malignancies. However, results from the published single studies are inconsistent. Therefore, the present meta-analysis was conducted to get a more accurate estimation of the relationship between CTLA-4 gene polymorphisms and the lymphoid malignancy risk. We identified nine independent studies accounting for 3090 subjects up to January 30, 2016. Summary odds ratios (OR) and 95 % confidence intervals (CI) were used to evaluate the risk of lymphoid malignancies. Overall, no significant association was found between +49A/G (rs231775), -318C/T (rs5742909), and +6230A/G (rs3087243) CTLA-4 gene polymorphisms and lymphoid malignancies. Furthermore, ethnicity (Asian and Caucasian) and histopathology subgroup analyses (non-Hodgkin's lymphoma) also failed to detect an association between the studied polymorphisms and lymphoid malignancy risk. Our study shows that common CTLA-4 gene polymorphisms may not contribute to lymphoid malignancy susceptibility based on the current evidence.

Medinger M, Halter J, Heim D, et al.
Gene-expression Profiling in Patients with Plasma Cell Myeloma Treated with Novel Agents.
Cancer Genomics Proteomics. 2016 Jul-Aug; 13(4):275-9 [PubMed] Related Publications
BACKGROUND/AIM: Novel agents such as thalidomide, lenalidomide and bortezomib have in part anti-angiogenic properties. In this study, we examined gene expression of angiogenic molecules in patients with plasma cell myeloma (PCM).
MATERIALS AND METHODS: We included 93 patients with PCM treated with novel agents (immunomodulatory drugs (IMiDs), bortezomib or a combination of both). The mRNA levels of angiogenic molecules were measured using the Human Angiogenesis RT2 Profiler PCR Array. The response evaluation was performed after three cycles.
RESULTS: Regarding all 93 patients, gene expression of 15 out of 84 genes tested (pre- and post-treatment and changes in levels pre-treatment/post-treatment) were significantly different in responders compared to non-responders. Responders had a lower expression of pro-angiogenic factors and increased expression of antiangiogenic factors.
CONCLUSION: In the IMiD-treated groups we found significant changes of expression of angiogenic genes in responders compared to non-responders, whereas in the bortezomib-based group the difference in expression of angiogenic genes was not significant.

Wang BB, Wu T
[Role of Biology Based on Epigenetics in Multiple Myeloma].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2016; 24(3):939-44 [PubMed] Related Publications
Multiple myeloma (MM) is a malignant tumor, characterized by dysplasia of clonal plasma cells in the bone marrow secreting large amounts of monoclonal immunoglobulin or fragments (M protein), resulting in damage in relevant organs or tissues. The biological complexity of MM is based on disrupted cancer pathways. Except the central role of cytogenetic abnormalities, epigenetic aberrations have also been shown to be involved in the occurrence and development of MM. Epigenetics of MM is mainly concentrated in the ways of DNA methylation, histone modifications and noncoding RNA, which have generated abnormal signaling pathways to regulate cell cycle and apoptosis of MM. In this article, advances of research on epigenetics of development, clinical diagnosis and treatments of MM are reviewed.

Furukawa Y, Kikuchi J
Epigenetic regulation of cell adhesion-mediated drug resistance acquisition in multiple myeloma.
Rinsho Ketsueki. 2016; 57(5):546-55 [PubMed] Related Publications
Elucidation of the epigenetic mechanisms underlying drug resistance may greatly contribute to the advancement of cancer therapies. In the present study, we identified trimethylation of histone H3 at lysine-27 (H3K27me3) as a critical histone modification for cell adhesion-mediated drug resistance (CAM-DR), which is the most important form of drug resistance in multiple myeloma. Cell adhesion counteracted drug-induced hypermethylation of H3K27 via inactivating phosphorylation of EZH2, leading to sustained expression of anti-apoptotic genes including IGF1, BCL2 and HIF1A. Inhibition of the IGF-1R/PI3K/Akt pathway reversed CAM-DR by promoting EZH2 dephosphorylation and H3K27 hypermethylation both in vitro and in refractory murine myeloma models. To our knowledge, this is the first demonstration of an epigenetic mechanism underlying CAM-DR and provides a rationale for the inclusion of kinase inhibitors counteracting EZH2 phosphorylation in combination chemotherapy aimed at increasing the therapeutic index.

Szalat R, Munshi NC
Next-Generation Sequencing Informing Therapeutic Decisions and Personalized Approaches.
Am Soc Clin Oncol Educ Book. 2016; 35:e442-8 [PubMed] Related Publications
Multiple myeloma is a heterogeneous disease featured by different molecular subtypes. In the last decade, new therapeutics including second- and third-generation proteasome inhibitors and immunomodulatory agents, monoclonal antibodies, and other novel targeted agents have completely transformed the outcome of the disease. The task ahead is to develop strategies to identify effective combinations and sequences of agents that can exploit the genetic make-up of myeloma cells to improve efficacy. Moreover, a subgroup of high-risk patients who experience early disease relapse and shorter survival also requires early identification and specific intervention. Next-generation sequencing (NGS) technologies now allow us to accomplish some of these goals. As described here, besides improving our understanding of the disease, it is beginning to influence our clinical decisions and therapeutic choices. In this article, we describe the current state-of-the-art role of NGS in myeloma from identifying high-risk disease, to drug selection, and, ultimately, to guide personalized therapy.

El-Ghammaz AM, Abdelwahed E
Bortezomib-based induction improves progression-free survival of myeloma patients harboring 17p deletion and/or t(4;14) and overcomes their adverse prognosis.
Ann Hematol. 2016; 95(8):1315-21 [PubMed] Related Publications
Providing a risk-adapted treatment strategy has been a key goal in the ongoing research efforts aimed at providing treatment tailored to the individual genetic make-up. Eighty myeloma patients have been tested for presence of 17p deletion and/or t(4;14) by fluorescent in situ hybridization (FISH). Based on FISH results, they have been categorized into patients lacking them (standard risk) and those harboring them (high risk). Patients in each category were randomly assigned 1:1 to induction treatment by either vincristine, adriamycin and dexamethasone (VAD), or bortezomib and dexamethasone (VD) followed by autologous stem cell transplantation and thalidomide maintenance and were followed up for 32 months. 32.5 % of patients were high risk. Following induction, there were significantly higher rates of at least very good partial response achievement in VD arms in standard- and high-risk patients. Regarding complete response achievement, there were insignificant differences between VAD and VD arms in standard and high-risk patients. After a median follow-up of 17.5 months, there was insignificant difference in overall survival (OS) between VAD and VD arms in standard and high-risk patients. There was superior progression-free survival (PFS) in VD arms in standard- and high-risk patients. Among patients who received VD, those belonging to standard and high-risk groups had similar PFS. In conclusion, bortezomib-based induction is superior to non-bortezomib-based one in patients harboring 17p deletion and/or t(4;14) in terms of improving PFS but not OS. Also, it reduces progression risk in patients harboring these high risk cytogenetics.

Jian Y, Chen X, Zhou H, et al.
Prognostic Impact of Cytogenetic Abnormalities in Multiple Myeloma: A Retrospective Analysis of 229 Patients.
Medicine (Baltimore). 2016; 95(19):e3521 [PubMed] Free Access to Full Article Related Publications
The identification of specific cytogenetic abnormalities by interphase fluorescence in situ hybridization (i-FISH) has become a routine procedure for prognostic stratification of multiple myeloma (MM) patients. In this study, the prognostic significance of cytogenetic abnormalities detected by interphase fluorescence in situ hybridization (iFISH) in 229 newly diagnosed multiple myeloma patients was retrospectively analyzed. Results showed that del (17p), t(4;14), and 1q21 gain were adverse predictors of progression-free survival (PFS). Patients who carried these cytogenetic abnormalities were more likely to have more adverse biological parameters and lower response rate. Multivariate analysis showed that del (17p), t(4;14), and 1q21 gain were statistically independent predictors of PFS, whereas del (17p) was also adverse predictor of overall survival. Multiple coexisting cytogenetic abnormalities also had a negative correlation with PFS. Bortezomib-based therapy could improve the rate and depth of response in patients with t(4;14) translocation and 1q21 gain. Autologous stem cell transplantation could improve, but not overcome the adverse prognostic effect of high-risk cytogenetic abnormalities. These results demonstrate that MM patients with iFISH abnormalities, especially del (17p), are more likely to have a poor prognosis.

Hatsuse M, Fuchida S, Okano A, et al.
[Transition to aggressive phase in a multiple myeloma patient with IgH/CCND1 translocation and diffuse osteosclerotic lesions].
Rinsho Ketsueki. 2016; 57(4):483-8 [PubMed] Related Publications
CASE: A 71-year-old woman had been diagnosed as having osteosclerotic myeloma (BJP-λ type) three years prior to the current presentation, based on tumor biopsy from the forehead showing plasmacytoma with systemic osteosclerotic lesions. At 71 years of age, she underwent transverse colectomy for a tumor in the hepatic flexure of the large intestine, and it was diagnosed as IgH/CCND-1-positive plasmacytoma of the large intestine. Although serum vascular endothelial cell growth factor (VEGF) was not elevated, the plasmacytoma was largely positive for VEGF staining. She subsequently experienced transformation to aggressive myeloma over a short period of time. Osteosclerotic myeloma is a rare disease that accounts for less than 3% of all myelomas, and requires differentiation from POEMS syndrome. In this case, peripheral nerve symptoms, which are necessary for the diagnosis of POEMS syndrome, were not confirmed. Thus, this case was diagnosed as having osteosclerotic myeloma. By contrast, abnormal IgH/CCND-1 is confirmed in 15% of patients with myeloma, and 25% of those with POEMS syndrome. While it is unclear whether this genetic abnormality is involved in the development of an osteosclerotic lesion, it is expected that data from patients with osteosclerotic myeloma and POEMS syndrome will be accumulated in the future, allowing clarification of the relationship between the genetic abnormality and osteosclerosis.

Xu Q, Hou YX, Langlais P, et al.
Expression of the cereblon binding protein argonaute 2 plays an important role for multiple myeloma cell growth and survival.
BMC Cancer. 2016; 16:297 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Immunomodulatory drugs (IMiDs), such as lenalidomide, are therapeutically active compounds that bind and modulate the E3 ubiquitin ligase substrate recruiter cereblon, thereby affect steady-state levels of cereblon and cereblon binding partners, such as ikaros and aiolos, and induce many cellular responses, including cytotoxicity to multiple myeloma (MM) cells. Nevertheless, it takes many days for MM cells to die after IMiD induced depletion of ikaros and aiolos and thus we searched for other cereblon binding partners that participate in IMiD cytotoxicity.
METHODS: Cereblon binding partners were identified from a MM cell line expressing histidine-tagged cereblon by pulling down cereblon and its binding partners and verified by co-immunoprecipitation. IMiD effects were determined by western blot analysis, cell viability assay, microRNA array and apoptosis analysis.
RESULTS: We identified argonaute 2 (AGO2) as a cereblon binding partner and found that the steady-state levels of AGO2 were regulated by cereblon. Upon treatment of IMiD-sensitive MM cells with lenalidomide, the steady-state levels of cereblon were significantly increased, whereas levels of AGO2 were significantly decreased. It has been reported that AGO2 plays a pivotal role in microRNA maturation and function. Interestingly, upon treatment of MM cells with lenalidomide, the steady-state levels of microRNAs were significantly altered. In addition, silencing of AGO2 in MM cells, regardless of sensitivity to IMiDs, significantly decreased the levels of AGO2 and microRNAs and massively induced cell death.
CONCLUSION: These results support the notion that the cereblon binding partner AGO2 plays an important role in regulating MM cell growth and survival and AGO2 could be considered as a novel drug target for overcoming IMiD resistance in MM cells.

Bilgrau AE, Falgreen S, Petersen A, et al.
Unaccounted uncertainty from qPCR efficiency estimates entails uncontrolled false positive rates.
BMC Bioinformatics. 2016; 17:159 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Accurate adjustment for the amplification efficiency (AE) is an important part of real-time quantitative polymerase chain reaction (qPCR) experiments. The most commonly used correction strategy is to estimate the AE by dilution experiments and use this as a plug-in when efficiency correcting the Δ Δ C q . Currently, it is recommended to determine the AE with high precision as this plug-in approach does not account for the AE uncertainty, implicitly assuming an infinitely precise AE estimate. Determining the AE with such precision, however, requires tedious laboratory work and vast amounts of biological material. Violation of the assumption leads to overly optimistic standard errors of the Δ Δ C q , confidence intervals, and p-values which ultimately increase the type I error rate beyond the expected significance level. As qPCR is often used for validation it should be a high priority to account for the uncertainty of the AE estimate and thereby properly bounding the type I error rate and achieve the desired significance level.
RESULTS: We suggest and benchmark different methods to obtain the standard error of the efficiency adjusted Δ Δ C q using the statistical delta method, Monte Carlo integration, or bootstrapping. Our suggested methods are founded in a linear mixed effects model (LMM) framework, but the problem and ideas apply in all qPCR experiments. The methods and impact of the AE uncertainty are illustrated in three qPCR applications and a simulation study. In addition, we validate findings suggesting that MGST1 is differentially expressed between high and low abundance culture initiating cells in multiple myeloma and that microRNA-127 is differentially expressed between testicular and nodal lymphomas.
CONCLUSIONS: We conclude, that the commonly used efficiency corrected quantities disregard the uncertainty of the AE, which can drastically impact the standard error and lead to increased false positive rates. Our suggestions show that it is possible to easily perform statistical inference of Δ Δ C q , whilst properly accounting for the AE uncertainty and better controlling the false positive rate.

Basmaci C, Pehlivan M, Tomatir A, et al.
Effects of TNFα, NOS3, MDR1 Gene Polymorphisms on Clinical Parameters, Prognosis and Survival of Multiple Myeloma Cases.
Asian Pac J Cancer Prev. 2016; 17(3):1009-14 [PubMed] Related Publications
It is not clear how gene polymorphisms affecting drugs can contributes totheir efficacy in multiple myeloma (MM). We here aimed to explore associations among gene polymorphisms of tumor necrosis factor alpha (TNFα), nitric oxide synthesis 3 (NOS3) and multi-drug resistance 1 (MDR1), clinical parameters, prognosis and survival in MM patients treated with VAD (vincristine-adriamycine-dexamethasone), MP (mephalane-prednisolone), autolougus stem cell transplantation (ASCT), BODEC (bortezomib-dexamethasone-cyclophosphamide) and TD (thalidomide-dexamethasone). We analyzed TNFα, NOS 3 and MDR1 in 77 patients with MM and 77 healthy controls. The genotyping was performed with PCR and/or PCR-RFLP. There was no clinically significant difference between MM and control groups when TNF α(-238) and (-857) and MDR1 gene polymorphisms were studied. However, the TNFαgene polymorphism (-308) GG genotype (p=0.012) and NOS3 (+894) TT genotype (p=0.008) were more common in the MM group compared to healthy controls. NOS3 (VNTR) AA (p=0.007) and NOS3 (+894) GG genotypes (p=0.004) were decreased in the MM group in contrast. In conclusion, the NOS3 (+894) TT and TNF α(-308) GG genotypes may have roles in myeloma pathogenesis.

Wang XG, Peng Y, Song XL, Lan JP
Identification potential biomarkers and therapeutic agents in multiple myeloma based on bioinformatics analysis.
Eur Rev Med Pharmacol Sci. 2016; 20(5):810-7 [PubMed] Related Publications
OBJECTIVE: The study aimed to identify potential therapeutic biomarkers and agents in multiple myeloma (MM) based on bioinformatics analysis.
MATERIALS AND METHODS: The microarray data of GSE36474 were downloaded from Gene Expression Omnibus database. A total of 4 MM and 3 normal bone marrow mesenchymal stromal cells (BM-MSCs) samples were used to identify the differentially expressed genes (DEGs). The hierarchical clustering analysis and functional enrichment analysis of DEGs were performed. Furthermore, co-expression network was constructed by Cytoscape software. The potential small molecular agents were identified with Connectivity Map (cMap) database.
RESULTS: A total of 573 DEGs were identified in MM samples comparing with normal samples, including 322 down- and 251 up-regulated genes. The DEGs were separated into two clusters. Down-regulated genes were mainly enriched in cell cycle function, while up-regulated genes were related to immune response. Down-regulated genes such as checkpoint kinase 1 (CHEK1), MAD2 mitotic arrest deficient-like 1 (MAD2L1) and DBF4 zinc finger (DBF4) were identified in cell cycle-related co-expression network. Up-regulated gene of guanylate binding protein 1, interferon-inducible (GBP1) was a hub node in immune response-related co-expression network. Additionally, the small molecular agent vinblastine was identified in this study.
CONCLUSIONS: The genes such as CHEK1, MAD2L1, DBF4 and GBP1 may be potential therapeutic biomarkers in MM. Vinblastine may be a potential therapeutic agent in MM.

Marcus H, Attar-Schneider O, Dabbah M, et al.
Mesenchymal stem cells secretomes' affect multiple myeloma translation initiation.
Cell Signal. 2016; 28(6):620-30 [PubMed] Related Publications
Bone marrow mesenchymal stem cells' (BM-MSCs) role in multiple myeloma (MM) pathogenesis is recognized. Recently, we have published that co-culture of MM cell lines with BM-MSCs results in mutual modulation of phenotype and proteome (via translation initiation (TI) factors eIF4E/eIF4GI) and that there are differences between normal donor BM-MSCs (ND-MSCs) and MM BM-MSCs (MM-MSCs) in this crosstalk. Here, we aimed to assess the involvement of soluble BM-MSCs' (ND, MM) components, more easily targeted, in manipulation of MM cell lines phenotype and TI with specific focus on microvesicles (MVs) capable of transferring critical biological material. We applied ND and MM-MSCs 72h secretomes to MM cell lines (U266 and ARP-1) for 12-72h and then assayed the cells' (viability, cell count, cell death, proliferation, cell cycle, autophagy) and TI (factors: eIF4E, teIF4GI; regulators: mTOR, MNK1/2, 4EBP; targets: cyclin D1, NFκB, SMAD5, cMyc, HIF1α). Furthermore, we dissected the secretome into >100kDa and <100kDa fractions and repeated the experiments. Finally, MVs were isolated from the ND and MM-MSCs secretomes and applied to MM cell lines. Phenotype and TI were assessed. Secretomes of BM-MSCs (ND, MM) significantly stimulated MM cell lines' TI, autophagy and proliferation. The dissected secretome yielded different effects on MM cell lines phenotype and TI according to fraction (>100kDa- repressed; <100kDa- stimulated) but with no association to source (ND, MM). Finally, in analyses of MVs extracted from BM-MSCs (ND, MM) we witnessed differences in accordance with source: ND-MSCs MVs inhibited proliferation, autophagy and TI whereas MM-MSCs MVs stimulated them. These observations highlight the very complex communication between MM and BM-MSCs and underscore its significance to major processes in the malignant cells. Studies into the influential MVs cargo are underway and expected to uncover targetable signals in the regulation of the TI/proliferation/autophagy cascade.

Binder M, Rajkumar SV, Ketterling RP, et al.
Occurrence and prognostic significance of cytogenetic evolution in patients with multiple myeloma.
Blood Cancer J. 2016; 6:e401 [PubMed] Free Access to Full Article Related Publications
Cytogenetic evaluation at the time of diagnosis is essential for risk stratification in multiple myeloma, however little is known about the occurrence and prognostic significance of cytogenetic evolution during follow-up. We studied 989 patients with multiple myeloma, including 304 patients with at least two cytogenetic evaluations. Multivariable-adjusted regression models were used to assess the associations between the parameters of interest and cytogenetic evolution as well as overall survival. The prognostic significance of baseline cytogenetic abnormalities was most pronounced at the time of diagnosis and attenuated over time. In the patients with serial cytogenetic evaluations, the presence of t(11;14) at the time of diagnosis was associated with decreased odds of cytogenetic evolution during follow-up (odds ratio (OR)=0.22, 95% confidence interval (CI)=0.09-0.56, P=0.001), while the presence of at least one trisomy or tetrasomy was associated with increased odds (OR=2.96, 95% CI=1.37-6.42, P=0.006). The development of additional abnormalities during the 3 years following diagnosis was associated with increased subsequent mortality (hazard ratio=3.31, 95% CI=1.73-6.30, P<0.001). These findings emphasize the importance of the underlying clonal disease process for risk assessment and suggest that selected patients may benefit from repeated risk stratification.

Kortuem KM, Braggio E, Bruins L, et al.
Panel sequencing for clinically oriented variant screening and copy number detection in 142 untreated multiple myeloma patients.
Blood Cancer J. 2016; 6:e397 [PubMed] Free Access to Full Article Related Publications
We employed a customized Multiple Myeloma (MM)-specific Mutation Panel (M(3)P) to screen a homogenous cohort of 142 untreated MM patients for relevant mutations in a selection of disease-specific genes. M(3)Pv2.0 includes 77 genes selected for being either actionable targets, potentially related to drug-response or part of known key pathways in MM biology. We identified mutations in potentially actionable genes in 49% of patients and provided prognostic evidence of STAT3 mutations. This panel may serve as a practical alternative to more comprehensive sequencing approaches, providing genomic information in a timely and cost-effective manner, thus allowing clinically oriented variant screening in MM.

Zhai B, Zou DD, Yan JJ, et al.
[Cytogenetic Abnormalities and Outcomes of 117 Patients with Multiple Myeloma Detected by FISH].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2016; 24(1):127-30 [PubMed] Related Publications
OBJECTIVE: To analyze the cytogenetic abnormalities and prognostic outcomes of patients with multiple myeloma (MM) detected by fluorescence in situ hybridization (FISH).
METHODS: The clinical record of 117 newly-diagnosed patients with MM treated in department of hematology and geriatric hematology of our hospital for 7 years were collected, and their molecular cytogenetic abnormalities detected by FISH and the clinical outcome were analyzed retrospectively.
RESULTS: The detected rate of cytogenetic abnormality was 76.9%(90/117), the most common abnormality deteted by FISH was 1q21+ (71.1%), followed by 13q- (56.6%). The cross comparison method showed that 13q- and 17p13-, t(11;14) and t(4;14) were related respectively. All the patients with cytogenetic abnormalities showed no significant difference in the overall survival from cytogenetic normal patients.
CONCLUSION: The positive rate of molecular cytogenetic abnormalities detected by FISH in MM patients is high, but data from larger and longer studies are needed to evaluate the prognostic outcomes.

Raimondi L, De Luca A, Morelli E, et al.
MicroRNAs: Novel Crossroads between Myeloma Cells and the Bone Marrow Microenvironment.
Biomed Res Int. 2016; 2016:6504593 [PubMed] Free Access to Full Article Related Publications
Multiple myeloma (MM) is a hematologic malignancy of differentiated plasma cells that accumulate in the bone marrow, where a complex microenvironment made by different cell types supports proliferation, survival, and drug resistance of tumor cells. MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression at posttranscriptional level. Emerging evidence indicates that miRNAs are aberrantly expressed or functionally deregulated in MM cells as the result of multiple genetic or epigenetic mechanisms and that also the tumor microenvironment regulates MM cell functions by miRNAs. Consistently, modulation of miRNA levels in MM cells has been demonstrated to impair their functional interaction with the bone marrow microenvironment and to produce significant antitumor activity even able to overcome the protective bone marrow milieu. This review will describe the most recent findings on miRNA function in the context of MM bone marrow microenvironment, focusing on the therapeutic potential of miRNA-based approaches.

Bartee MY, Dunlap KM, Bartee E
Myxoma Virus Induces Ligand Independent Extrinsic Apoptosis in Human Myeloma Cells.
Clin Lymphoma Myeloma Leuk. 2016; 16(4):203-12 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
INTRODUCTION: Multiple myeloma is a clonal malignancy of plasma B cells. Although recent advances have improved overall prognosis, virtually all myeloma patients still succumb to relapsing disease. Therefore, novel therapies to treat this disease remain urgently needed. We have recently shown that treatment of human multiple myeloma cells with an oncolytic virus known as myxoma results in rapid cell death even in the absence of viral replication; however, the specific mechanisms and pathways involved remain unknown.
MATERIALS AND METHODS: To determine how myxoma virus eliminates human multiple myeloma cells, we queried the apoptotic pathways that were activated after viral infection using immunoblot analysis and other cell biology approaches.
RESULTS: Our results indicate that myxoma virus infection initiates apoptosis in multiple myeloma cells through activation of the extrinsic initiator caspase-8. Caspase-8 activation subsequently results in cleavage of BH3 interacting-domain death agonist and loss of mitochondrial membrane potential causing secondary activation of caspase-9. Activation of caspase-8 appears to be independent of extrinsic death ligands and instead correlates with depletion of cellular inhibitors of apoptosis. We hypothesize that this depletion results from virally mediated host-protein shutoff because a myxoma construct that overexpresses the viral decapping enzymes displays improved oncolytic potential.
CONCLUSION: Taken together, these results suggest that myxoma virus eliminates human multiple myeloma cells through a pathway unique to oncolytic poxviruses, making it an excellent therapeutic option for the treatment of relapsed or refractory patients.

Fulciniti M, Amodio N, Bandi RL, et al.
miR-23b/SP1/c-myc forms a feed-forward loop supporting multiple myeloma cell growth.
Blood Cancer J. 2016; 6:e380 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Deregulated microRNA (miR)/transcription factor (TF)-based networks represent a hallmark of cancer. We report here a novel c-Myc/miR-23b/Sp1 feed-forward loop with a critical role in multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM) cell growth and survival. We have found miR-23b to be downregulated in MM and WM cells especially in the presence of components of the tumor bone marrow milieu. Promoter methylation is one mechanism of miR-23b suppression in myeloma. In gain-of-function studies using miR-23b mimics-transfected or in miR-23b-stably expressing MM and WM cell lines, we observed a significant decrease in cell proliferation and survival, along with induction of caspase-3/7 activity over time, thus supporting a tumor suppressor role for miR-23b. At the molecular level, miR-23b targeted Sp1 3'UTR and significantly reduced Sp1-driven nuclear factor-κB activity. Finally, c-Myc, an important oncogenic transcription factor known to stimulate MM cell proliferation, transcriptionally repressed miR-23b. Thus MYC-dependent miR-23b repression in myeloma cells may promote activation of oncogenic Sp1-mediated signaling, representing the first feed-forward loop with critical growth and survival role in myeloma.

Yokoi S, Sakai H, Uchida A, et al.
Cytogenetic Study and Analysis of Protein Expression in Plasma Cell Myeloma with t(11;14)(q13;q32): Absence of BCL6 and SOX11, and Infrequent Expression of CD20 and PAX5.
J Clin Exp Hematop. 2015; 55(3):137-43 [PubMed] Related Publications
The t(11;14)(q13;q32) translocation is the most common chromosomal translocation in plasma cell myeloma (PCM), but the cytogenetic and immunophenotypic features of PCM with t(11;14)(q13;q32) remain to be fully elucidated. To address the issue, we retrospectively analyzed 21 newly diagnosed PCM patients with the t(11;14)(q13;q32) translocation in our institute. CD20 is a B-cell-specific transmembrane protein that is the topic of much focus as a potential target in immunotherapy. We observed a low incidence of CD20 expression (2 of 21 patients, 11%), although the expression of CD20 was previously reported to be associated with t(11;14)(q13;q32). PAX5 is an essential transcriptional factor involved in B-cell development and commitment, and is down-regulated upon plasma cell differentiation. We observed one patient (6%) with expression of PAX5. The expression of CD19, CD56, and CD138 was detected in one (0.7%), nine (60%), and 13 patients (87%), respectively. Cyclin D1, CD38, and BCL2 were detected in all patients; on the other hand, neither BCL6 nor SOX11 was detected in any of the evaluated patients. Abnormalities of chromosome 13 were detected in six patients (38%), but deletion of TP53 was not observed in any of the evaluated patients. Our results suggest the absence of BCL6 and SOX11 expression, and infrequent expression of CD20, PAX5, and CD56 in PCM with t(11;14)(q13;q32), in contrast to the findings of earlier reports.

Tsubaki M, Takeda T, Yoshizumi M, et al.
RANK-RANKL interactions are involved in cell adhesion-mediated drug resistance in multiple myeloma cell lines.
Tumour Biol. 2016; 37(7):9099-110 [PubMed] Related Publications
Interaction between multiple myeloma (MM) cells and the bone marrow microenvironment plays a critical role in MM pathogenesis and the development of drug resistance. Recently, it has been reported that MM cells express the receptor activator of nuclear factor-κB (NF-κB) (RANK). However, the role of the RANK/RANK ligand (RANKL) system in drug resistance remains unclear. In this study, we demonstrated a novel function of the RANK/RANKL system in promoting drug resistance in MM. We found that RANKL treatment induced drug resistance in RANK-expressing but not RANK-negative cell lines. RANKL stimulation of RANK-expressing cells increased multidrug resistance protein 1 (MDR1), breast cancer resistance protein (BCRP), and lung resistance protein 1 (LRP1) expression and decreased Bim expression through various signaling molecules. RNA silencing of Bim expression induced drug resistance, but the RANKL-mediated drug resistance could not be overcome through the RNA silencing of MDR1, BCRP, and LRP1 expression. These results indicate that the RANK/RANKL system induces chemoresistance through the activation of multiple signal transduction pathways and by decreasing Bim expression in RANK-positive MM cells. These findings may prove to be useful in the development of cell adhesion-mediated drug resistance inhibitors in RANK-positive MM cells.

Paiva B, Corchete LA, Vidriales MB, et al.
Phenotypic and genomic analysis of multiple myeloma minimal residual disease tumor cells: a new model to understand chemoresistance.
Blood. 2016; 127(15):1896-906 [PubMed] Related Publications
Persistence of chemoresistant minimal residual disease (MRD) plasma cells (PCs) is associated with inferior survival in multiple myeloma (MM). Thus, characterization of the minor MRD subclone may represent a unique model to understand chemoresistance, but to our knowledge, the phenotypic and genetic features of the MRD subclone have never been investigated. Here, we compared the antigenic profile of MRD vs diagnostic clonal PCs in 40 elderly MM patients enrolled in the GEM2010MAS65 study and showed that the MRD subclone is enriched in cells overexpressing integrins (CD11a/CD11c/CD29/CD49d/CD49e), chemokine receptors (CXCR4), and adhesion molecules (CD44/CD54). Genetic profiling of MRD vs diagnostic PCs was performed in 12 patients; 3 of them showed identical copy number alterations (CNAs), in another 3 cases, MRD clonal PCs displayed all genetic alterations detected at diagnosis plus additional CNAs that emerged at the MRD stage, whereas in the remaining 6 patients, there were CNAs present at diagnosis that were undetectable in MRD clonal PCs, but also a selected number of genetic alterations that became apparent only at the MRD stage. The MRD subclone showed significant downregulation of genes related to protein processing in endoplasmic reticulum, as well as novel deregulated genes such as ALCAM that is prognostically relevant in MM and may identify chemoresistant PCs in vitro. Altogether, our results suggest that therapy-induced clonal selection could be already present at the MRD stage, where chemoresistant PCs show a singular phenotypic signature that may result from the persistence of clones with different genetic and gene expression profiles. This trial was registered atwww.clinicaltrials.gov as #NCT01237249.

Agarwal P, Alzrigat M, Párraga AA, et al.
Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.
Oncotarget. 2016; 7(6):6809-23 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Multiple myeloma (MM) is a malignancy of the antibody-producing plasma cells. MM is a highly heterogeneous disease, which has hampered the identification of a common underlying mechanism for disease establishment as well as the development of targeted therapy. Here we present the first genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in MM patient samples, defining a common set of active H3K4me3-enriched genes and silent genes marked by H3K27me3 (H3K27me3 alone or bivalent) unique to primary MM cells, when compared to normal bone marrow plasma cells. Using this epigenome profile, we found increased silencing of H3K27me3 targets in MM patients at advanced stages of the disease, and the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also demonstrated that pharmacological inhibition of EZH2 had anti-myeloma effects in both MM cell lines and CD138+ MM patient cells. In addition, EZH2 inhibition decreased the global H3K27 methylation and induced apoptosis. Taken together, these data suggest an important role for the Polycomb repressive complex 2 (PRC2) in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.

Johnson DC, Weinhold N, Mitchell JS, et al.
Genome-wide association study identifies variation at 6q25.1 associated with survival in multiple myeloma.
Nat Commun. 2016; 7:10290 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Survival following a diagnosis of multiple myeloma (MM) varies between patients and some of these differences may be a consequence of inherited genetic variation. In this study, to identify genetic markers associated with MM overall survival (MM-OS), we conduct a meta-analysis of four patient series of European ancestry, totalling 3,256 patients with 1,200 MM-associated deaths. Each series is genotyped for ∼600,000 single nucleotide polymorphisms across the genome; genotypes for six million common variants are imputed using 1000 Genomes Project and UK10K as the reference. The association between genotype and OS is assessed by Cox proportional hazards model adjusting for age, sex, International staging system and treatment. We identify a locus at 6q25.1 marked by rs12374648 associated with MM-OS (hazard ratio=1.34, 95% confidence interval=1.22-1.48, P=4.69 × 10(-9)). Our findings have potential clinical implications since they demonstrate that inherited genotypes can provide prognostic information in addition to conventional tumor acquired prognostic factors.

Raninga PV, Di Trapani G, Vuckovic S, Tonissen KF
TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition.
Cell Cycle. 2016; 15(4):559-72 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Multiple myeloma (MM) is a B-cell malignancy characterized by an accumulation of abnormal clonal plasma cells in the bone marrow. Introduction of the proteasome-inhibitor bortezomib has improved MM prognosis and survival; however hypoxia-induced or acquired bortezomib resistance remains a clinical problem. This study highlighted the role of thioredoxin reductase 1 (TrxR1) in the hypoxia-induced and acquired bortezomib resistance in MM. Higher TrxR1 gene expression correlated with high-risk disease, adverse overall survival, and poor prognosis in myeloma patients. We demonstrated that hypoxia induced bortezomib resistance in myeloma cells and increased TrxR1 protein levels. Inhibition of TrxR1 using auranofin overcame hypoxia-induced bortezomib resistance and restored the sensitivity of hypoxic-myeloma cells to bortezomib. Hypoxia increased NF-кβ subunit p65 nuclear protein levels and TrxR1 inhibition decreased hypoxia-induced NF-кβ p65 protein levels in the nucleus and reduced the expression of NF-кβ-regulated genes. In addition, higher TrxR1 protein levels were observed in bortezomib-resistant myeloma cells compared to the naïve cells, and its inhibition using either auranofin or TrxR1-specific siRNAs reversed bortezomib resistance. TrxR1 inhibition reduced p65 mRNA and protein expression in bortezomib-resistant myeloma cells, and also decreased the expression of NF-кβ-regulated anti-apoptotic and proliferative genes. Thus, TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance by inhibiting the NF-кβ signaling pathway. Our findings demonstrate that elevated TrxR1 levels correlate with the acquisition of bortezomib resistance in MM. We propose considering TrxR1-inhibiting drugs, such as auranofin, either for single agent or combination therapy to circumvent bortezomib-resistance and improve survival outcomes of MM patients.

Edwards SK, Han Y, Liu Y, et al.
Signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells.
Leuk Res. 2016; 41:85-95 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Bortezomib, a clinical drug for multiple myeloma (MM) and mantle cell lymphoma, exhibits complex mechanisms of action, which vary depending on the cancer type and the critical genetic alterations of each cancer. Here we investigated the signaling mechanisms of bortezomib in mouse B lymphoma and human MM cells deficient in a new tumor suppressor gene, TRAF3. We found that bortezomib consistently induced up-regulation of the cell cycle inhibitor p21(WAF1) and the pro-apoptotic protein Noxa as well as cleavage of the anti-apoptotic protein Mcl-1. Interestingly, bortezomib induced the activation of NF-κB1 and the accumulation of the oncoprotein c-Myc, but inhibited the activation of NF-κB2. Furthermore, we demonstrated that oridonin (an inhibitor of NF-κB1 and NF-κB2) or AD 198 (a drug targeting c-Myc) drastically potentiated the anti-cancer effects of bortezomib in TRAF3-deficient malignant B cells. Taken together, our findings increase the understanding of the mechanisms of action of bortezomib, which would aid the design of novel bortezomib-based combination therapies. Our results also provide a rationale for clinical evaluation of the combinations of bortezomib and oridonin (or other inhibitors of NF-κB1/2) or AD 198 (or other drugs targeting c-Myc) in the treatment of lymphoma and MM, especially in patients containing TRAF3 deletions or relevant mutations.

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 (20q12)

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.

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)

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.

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.

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)

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.

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