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.

Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (81)

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
FGFR3 4p16.3 ACH, CEK2, JTK4, CD333, HSFGFR3EX -FGFR3 and Multiple Myeloma
TNFRSF11B 8q24 OPG, TR1, OCIF -TNFRSF11B 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, CTRCT21 -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
CCND3 6p21 -CCND3 and Multiple Myeloma
IGL 22q11.2 IGL@, IGLC6 -IGL and Multiple Myeloma
CKS1B 1q21.2 CKS1, ckshs1, PNAS-16, PNAS-18 -CKS1B and Multiple Myeloma
CCL3 17q12 MIP1A, SCYA3, G0S19-1, LD78ALPHA, MIP-1-alpha -CCL3 and Multiple Myeloma
IGK 2p12 IGK@ -IGK 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
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
TRAF3 14q32.32 CAP1, LAP1, CAP-1, CRAF1, IIAE5, CD40bp -TRAF3 and Multiple Myeloma
MUM1 19p13.3 MUM-1, EXPAND1, HSPC211 -MUM1 and Multiple Myeloma
B2M 15q21.1 -B2M and Multiple Myeloma
XBP1 22q12.1 XBP2, TREB5, XBP-1, TREB-5 -XBP1 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
FRZB 2q32.1 FRE, OS1, FZRB, hFIZ, FRITZ, FRP-3, FRZB1, SFRP3, SRFP3, FRZB-1, FRZB-PEN -FRZB 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
CYP2C8 10q23.33 CPC8, CYPIIC8, MP-12/MP-20 -CYP2C8 and Multiple Myeloma
ITGA4 2q31.3 IA4, CD49D -ITGA4 and Multiple Myeloma
CDR2 16p12.3 Yo, CDR62 -CDR2 and Multiple Myeloma
FAM46C 1p12 -FAM46C 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
BIRC2 11q22 API1, MIHB, HIAP2, RNF48, cIAP1, Hiap-2, c-IAP1 -BIRC2 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
CD200 3q13.2 MRC, MOX1, MOX2, OX-2 -CD200 and Multiple Myeloma
MERTK 2q14.1 MER, RP38, c-Eyk, c-mer, Tyro12 -MERTK and Multiple Myeloma
NR3C1 5q31.3 GR, GCR, GRL, GCCR, GCRST -NR3C1 and Multiple Myeloma
IL6R 1q21 IL6Q, gp80, CD126, IL6RA, IL6RQ, IL-6RA, IL-6R-1 -IL6R and Multiple Myeloma
TLR1 4p14 TIL, CD281, rsc786, TIL. LPRS5 -TLR1 and Multiple Myeloma
ITGAL 16p11.2 CD11A, LFA-1, LFA1A -ITGAL and Multiple Myeloma
JAG2 14q32 HJ2, SER2 -JAG2 and Multiple Myeloma
FCGR2A 1q23 CD32, FCG2, FcGR, CD32A, CDw32, FCGR2, IGFR2, FCGR2A1 -FCGR2A and Multiple Myeloma
BAGE 21p11.1 not on ref BAGE1, CT2.1 -BAGE and Multiple Myeloma
IL21 4q26-q27 Za11, IL-21, CVID11 -IL21 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
PIAS3 1q21 ZMIZ5 -PIAS3 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
SLC7A5 16q24.3 E16, CD98, LAT1, 4F2LC, MPE16, hLAT1, D16S469E -SLC7A5 and Multiple Myeloma
ADAMTS9 3p14.1 -ADAMTS9 and Multiple Myeloma
RNF217-AS1 6q22.33 STL -STL and Multiple Myeloma
KL 13q12 -KL and Multiple Myeloma
CD47 3q13.1-q13.2 IAP, OA3, MER6 -CD47 and Multiple Myeloma
SLAMF1 1q23.3 SLAM, CD150, CDw150 -SLAMF1 and Multiple Myeloma
MIR106B 7q22.1 MIRN106B -MIR106B 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 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

Nazarova EL, Shardakov VI, Dem'ianova VT, et al.
[The diagnostic of defects of inborn immunity under B-cell tumors of lymphatic system].
Klin Lab Diagn. 2014; 59(11):39-42 [PubMed] Related Publications
The genetic characteristics are key risk factors of development of many human neoplasms including B-cell tumors of lymphatic system. The relationship between polymorphic variants of genes FCGR2A (His 1 66Agr), CD14 (C-159T). IL1β (T-31C), IL2 (7:330G) and 7LR2 (Arg753Ghn) and development of various forms of B-cell tumors of lymphatic system in 80 patients was investigated. The statistically significant differences of rates of particiular genotypes of single nucleotid polymorphisms of genes FCGR2A, CD14. IL1β, IL2 and TLR2 in patients with indolent and aggressive types of course of non-Hodgkin lymphoma and also multiple myeloma. The results prove hypothesis that genetic variants of genes of inborn immune response effect the origin and character of course of different types of lymphoproliferative diseases. The markers can become additional prognostic characteristics of benign and aggressive course of tumors.

He H, Fu W, Jiang H, et al.
The clinical characteristics and prognosis of IGH deletion in multiple myeloma.
Leuk Res. 2015; 39(5):515-9 [PubMed] Related Publications
OBJECTIVE: To analyze the frequency, clinical characteristics, and prognosis of IGH deletion in multiple myeloma (MM).
METHODS: A total of 310 consecutive patients with multiple myeloma were analyzed. Among them 251 patients were newly diagnosed and 59 patients were previously treated, fluorescence in situ hybridization (FISH) with IGH break apart probes were done for each case. Patterns of IGH deletion, response rate, overall survival, and progression free survival were analyzed.
RESULTS: Several patterns of IGH deletion were identified, including monoallelic deletion of whole locus of IGH, monoallelic deletion of 3' IGH, monoallelic deletion of 5' IGH, biallelic deletion of 3' IGH deletion, and complicated deletions with various types. The incidence rate of IGH deletion was 22.7% (57/251) in newly diagnosed patients and 27.2% (16/59) in previously treated patients, no significant difference was found between the two groups (p=0.375). IGH deletion was associated with κ light chain M component (p<0.001), 13q deletion (p=0.006), and absence of t(4; 14)(p=0.033). In the cases with 13q deletion, the frequency of IGH deletion is 3.5% (1/28) in patients with t(4;14) and 40.5% (32/79) in patients without t(4;14), significant difference was found (p=0.006). We further analyzed the response rates of patients with IGH deletion who received a uniform induction regimen of PAD composing of bortezomib, epirubicin, and dexamethasone. Overall response rate (ORR) in patients with IGH deletion was better than that in patients without IGH deletion (87.5 vs. 73.6%, p<0.001), while no significant difference was found in survival analysis, either OS or PFS (p=0.158 and p=0.177, respectively).
CONCLUSION: IGH deletion is frequent in multiple myeloma, the incidence rate was higher in patients with 13q deletion and without t(4;14). Patients with IGH deletion had better ORR to PAD induction therapy, while it has no influence on the prognosis of multiple myeloma.

Kortüm KM, Langer C, Monge J, et al.
Longitudinal analysis of 25 sequential sample-pairs using a custom multiple myeloma mutation sequencing panel (M(3)P).
Ann Hematol. 2015; 94(7):1205-11 [PubMed] Related Publications
Recent advances in genomic sequencing technologies now allow results from deep next-generation sequencing to be obtained within clinically meaningful timeframes, making this an attractive approach to better guide personalized treatment strategies. No multiple myeloma-specific gene panel has been established so far; we therefore designed a 47-gene-targeting gene panel, containing 39 genes known to be mutated in ≥3 % of multiple myeloma cases and eight genes in pathways therapeutically targeted in multiple myeloma (MM). We performed targeted sequencing on tumor/germline DNA of 25 MM patients in which we also had a sequential sample post treatment. Mutation analysis revealed KRAS as the most commonly mutated gene (36 % in each time point), followed by NRAS (20 and 16 %), TP53 (16 and 16 %), DIS3 (16 and 16 %), FAM46C (12 and 16 %), and SP140 (12 and 12 %). We successfully tracked clonal evolution and identified mutation acquisition and/or loss in FAM46C, FAT1, KRAS, NRAS, SPEN, PRDM1, NEB, and TP53 as well as two mutations in XBP1, a gene associated with bortezomib resistance. Thus, we present the first longitudinal analysis of a MM-specific targeted sequencing gene panel that can be used for individual tumor characterization and for tracking clonal evolution over time.

Hebraud B, Magrangeas F, Cleynen A, et al.
Role of additional chromosomal changes in the prognostic value of t(4;14) and del(17p) in multiple myeloma: the IFM experience.
Blood. 2015; 125(13):2095-100 [PubMed] Article available free on PMC after 26/03/2016 Related Publications
In multiple myeloma, cytogenetic changes are important predictors of patient outcome. In this setting, the most important changes are deletion 17p, del(17p), and translocation of chromosomes 4 and 14, t(4;14), conferring a poor outcome. However, a certain degree of heterogeneity is observed in the survival of these high-risk patients. We hypothesized that other chromosomal changes may impact the outcome. We retrospectively analyzed a large series of 242 patients displaying either t(4;14) (157 patients) or del(17p) (110 patients), 25 patients presenting both abnormalities, using single nucleotide polymorphism array. In patients with t(4;14), del(1p32), del22q, and >30 chromosomal structural changes negatively impacted progression-free survival (PFS). For overall survival (OS), del(13q14), del(1p32), and the number of chromosomal structural changes worsened the prognosis of patients. For patients with del(17p), del6q worsened the prognosis of patients, whereas trisomy 15 and monosomy 14 were found to have a protective effect on PFS. For OS, del(1p32) worsened the prognosis of patients, whereas having >8 numerical changes was found to have a protective effect on survival. This study, which is the largest series of high-risk patients analyzed with the most modern genomic technique, identified 1 main factor negatively impacting survival: del(1p32).

Kumar S
Blind men and an elephant.
Blood. 2015; 125(5):745-7 [PubMed] Related Publications
In this issue of Blood, Pawlyn et al examine the prognostic implications of overlapping chromosomal abnormalities in multiple myeloma (MM), demonstrating that coexistence of hyperdiploidy does not mitigate the impact of high-risk abnormalities.

Corre J, Munshi N, Avet-Loiseau H
Genetics of multiple myeloma: another heterogeneity level?
Blood. 2015; 125(12):1870-6 [PubMed] Article available free on PMC after 19/03/2016 Related Publications
Our knowledge of myeloma genetics remained limited and lagged behind many other hematologic malignancies because of the inherent difficulties in generating metaphases within the malignant plasma cell clone. With the development of molecular techniques (microarrays and next-generation sequencing), our understanding has been highly improved in the past 5 years. These studies have not only confirmed the prevalence of wide heterogeneity in myeloma at the molecular level, but has also provided a much clearer picture of the disease pathogenesis and progression. Whether these data will enable improvements in the therapeutic approach is still a matter of debate. The next improvement will come from detailed analyses of these molecular features to try to move from a treatment fitted to every patient to individualized therapies, taking into account the complexity of the chromosomal changes, the mutation spectrum, and subclonality evolution.

Terui Y
[The epigenetic alteration and the effect of HDAC inhibitors in multiple myeloma].
Nihon Rinsho. 2015; 73(1):124-9 [PubMed] Related Publications
Epigenetic abnormalities are central players in the disruption of common cancer pathway, and epigenetic aberrations have also been shown to play an important role in development of multiple myeloma. DNA methylation, histone modifications contribute to the pathogenesis of multiple myeloma. Understanding of epigenetic abnormalities in myeloma leads to development of novel drugs such as histone deacetylase inhibitors (HDACi). Here I will discuss about common epigenetic mechanisms (aberrant DNA methylation, histone modifications), the epigenetic aberrations in myeloma and clinical development of novel drug HDACi.

Ishida T
[Cytogenetic abnormalities in high-risk multiple myeloma].
Nihon Rinsho. 2015; 73(1):28-32 [PubMed] Related Publications
Multiple myeloma is a genetically complex disease. Myeloma can be divided into hyperdiploid and non-hyperdiploid subtypes. Non-hyperdiploid subtype is mainly composed of cases harboring IgH translocations, generally associated with more aggressive clinical features and shorter survival. From a comprehensive FISH tests, the lesions associated with short progression-free survival and overall survival in multivariate analysis were del(17p13), abnormalities of chromosome 1(1p deletion and 1q amplification) and an adverse immunoglobulin heavy chain gene translocation group incorporating t(4;14), t(14;16) and t(14;20). Furthermore, the high frequency of mutations in the ERK pathway (NRAS in 24%, KRAS in 27% and BRAF in 4%) indicates that the ERK pathway is crucial for myeloma development.

Hanamura I, Iida S
[Classification and genetic abnormalities of multiple myeloma].
Nihon Rinsho. 2015; 73(1):17-27 [PubMed] Related Publications
Multiple myeloma (MM) is a malignancy of plasma cells which develops through genetic aberrations, epigenetic changes and the bone marrow microenvironment interaction. Despite recent tremendous progress in treatments for MM, a complete cure remains elusive. Further development of more effective therapeutic strategies is needed. The International Staging System (ISS) reported in 2005 has been used widely as the most simple and powerful prognostic classification in MM, but genetic abnormalities affecting prognosis were not considered in this model. In the past decade, non-random chromosomal aberrations such as t(4;14), t(14;16), t(14;20), amp1q21 and del17p have shown to be poor prognostic value, and moreover, recent progress in genome-wide deep sequencing studies has revealed novel mutations and intra-tumor subclonal heterogeneity which may explain clinical phenotype and therapeutic resistance. Here we review the current understanding of genetic abnormalities in MM for developing better prognostic classification and molecular targeted therapies leading to the stratified or personalized medicine.

Sata H, Shibayama H, Maeda I, et al.
Quantitative polymerase chain reaction analysis with allele-specific oligonucleotide primers for individual IgH VDJ regions to evaluate tumor burden in myeloma patients.
Exp Hematol. 2015; 43(5):374-381.e2 [PubMed] Related Publications
Quantitative polymerase chain reaction (PCR) with patient-specific, allele-specific oligonucleotide (ASO) primers for individual immunoglobulin H VDJ region (ASO-PCR) amplification was performed using several sources of clinical material, including mRNA from peripheral blood cells (PBMNCs), whole bone marrow cells (BMMNCs), and the CD20+ CD38- B-cell population in bone marrow, as well as cell-free DNA from the sera of patients with multiple myeloma (MM). We designed the ASO primers and produced sufficient PCR fragments to evaluate tumor burden in 20 of 30 bone marrow samples at diagnosis. Polymerase chain reaction amplification efficiency depended on primer sequences because the production of ASO-PCR fragments did not correlate with serum M-protein levels. However, the ASO-PCR levels in BMMNCs showed statistically significant correlations with those in PBMNCs and CD20+ CD38- B-cells. The good association between the BMMNC and PBMNC data indicated that PBMNCs could be a suitable source for monitoring minimal residual disease (MRD). In the case of cell-free DNA, ASO-PCR levels showed a unique pattern and remained high even after treatment. Because the sequence information for each ASO-PCR product was identical to the original, the cell-free DNA might also be useful for evaluating MRD. Moreover, the ASO-PCR products were clearly detected in 17 of 22 mRNA samples from CD20+ CD38- populations, suggesting that MM clones might exist in relatively earlier stages of B cells than in plasma cells. Thus, ASO-PCR analysis using various clinical materials is useful for detecting MRD in MM patients as well as for clarifying MM pathogenesis.

Weißbach S, Langer C, Puppe B, et al.
The molecular spectrum and clinical impact of DIS3 mutations in multiple myeloma.
Br J Haematol. 2015; 169(1):57-70 [PubMed] Related Publications
Multiple myeloma (MM) is a plasma cell neoplasm that presents with a major biological and clinical heterogeneity. We here investigated the spectrum of clonal and subclonal mutations of DIS3, an active part of the exosome complex, that may play a role in the development or progression of MM. The whole coding sequence of DIS3 was subjected to deep sequencing in 81 uniformly-treated MM patients and 12 MM cell lines and the overall occurrence of DIS3 mutations as well as the presence of DIS3 mutations in minor and major subclones were correlated with cytogenetic alterations and clinical parameters. Our study identified DIS3 mutations in 9/81 patients that were associated with 13q14 deletions and IGH translocations on the cytogenetic level. Specifically, we detected seven novel somatic DIS3 single nucleotide variants (SNVs) and defined three hot spot mutations within the RNB domain. Lastly, we found a trend towards a shorter median overall survival for patients with DIS3 mutations, and patients carrying DIS3 mutations in minor subclones of their tumours showed a significantly worse response to therapy compared to patients with DIS3 mutations in the major subclone.

Gu Z, Zhou W, Huang J, et al.
Nek2 is a novel regulator of B cell development and immunological response.
Biomed Res Int. 2014; 2014:621082 [PubMed] Article available free on PMC after 19/03/2016 Related Publications
The serine/threonine kinase Nek2 is commonly found upregulated in a wide variety of neoplasms including diffuse large B cell lymphoma and multiple myeloma. High expression of Nek2 is implicated in the induction of chromosomal instability, promotion of cell proliferation, and drug resistance in tumor cells as well as a marker for poor clinical outcomes. Despite its well recorded involvement in chromosomal instability and neoplastic growth, little is known about the involvement of Nek2 in B cell development. Here we report the development of a transgenic mouse line with conditional expression of Nek2 in the B cell lineage and the effects it has on the development of B cells. Interestingly, we found that the overexpression of Nek2 does not induce spontaneous tumor formation within the transgenic mice up to 24 months after induction. Instead, overexpression of Nek2 in the B cell lineage affects the development of B cells by increasing the proportion of immature B cells in the bone marrow and decreasing B-1 B cells in peritoneal cavity. Furthermore, Nek2 transgenic mice develop spontaneous germinal centers and exhibit an enhanced T cell dependent immune response. Altogether, our data demonstrates a novel role for Nek2 in regulating B cell development and the immune response.

Dhyani A, Machado-Neto JA, Favaro P, Saad ST
ANKHD1 represses p21 (WAF1/CIP1) promoter and promotes multiple myeloma cell growth.
Eur J Cancer. 2015; 51(2):252-9 [PubMed] Related Publications
ANKHD1 (Ankyrin repeat and KH domain-containing protein 1) is highly expressed and plays an important role in the proliferation and cell cycle progression of multiple myeloma (MM) cells. ANKHD1 downregulation modulates cell cycle gene expression and upregulates p21 irrespective of the TP53 mutational status of MM cell lines. The present study was aimed to investigate the role of ANKHD1 in MM in vitro clonogenicity and in vivo tumourigenicity, as well as the role of ANKHD1 in p21 transcriptional regulation. ANKHD1 silencing in MM cells resulted in significantly low no. of colonies formed and in slow migration as compared to control cells (p < 0.05). Furthermore, in xenograft MM mice models, tumour growth was visibly suppressed in mice injected with ANKHD1 silenced cells compared to the control group. There was a significant decrease in tumour volume (p = 0.006) as well as in weight (p = 0.02) in the group injected with silenced cells compared to those of the control group. Co-immunoprecipitation and chromatin immunoprecipitation (ChIP) assays confirmed the interaction between p21 and ANKHD1. Moreover, overexpression of ANKHD1 downregulated the activity of a p21 promoter in luciferase assays. Decrease in luciferase activity suggests a direct role of ANKHD1 in p21 transcriptional regulation. In addition confocal analysis after U266 cells were treated with Leptomycin B (LMB) for 24 h showed accumulation of ANKHD1 inside the nucleus as compared to untreated cells where ANKHD1 was found to be predominantly in cytoplasm. This suggests ANKHD1 might be shuttling between cytoplasm and nucleus. In conclusion, ANKHD1 promotes MM growth by repressing p21 a potent cell cycle regulator.

Shi Q, Wang XS, Li G, et al.
Racial/ethnic disparities in inflammatory gene single-nucleotide polymorphisms as predictors of a high risk for symptom burden in patients with multiple myeloma 1 year after diagnosis.
Cancer. 2015; 121(7):1138-46 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
BACKGROUND: This study was conducted to determine whether any regulatory single-nucleotide polymorphism (SNP) in an inflammatory gene was associated with a high symptom burden in patients 1 year after the diagnosis of multiple myeloma (MM).
METHODS: MM patients rated symptoms with the MD Anderson Symptom Inventory multiple myeloma module (MDASI-MM) and provided buccal-swab DNA samples. SNPs for 4 cytokine genes (interleukin 6 [IL6] -174G>C, IL1β -511C>T, tumor necrosis factor α [TNFα] -308G>A, and IL10 -1082G>A) were tested. Logistic regression models were used to identify SNPs that might predict moderate/severe symptoms (rated ≥ 4 on the MDASI-MM 0-10 scale). For the evaluation of the relationship between SNPs and overall symptom burden, a 2-step cluster analysis was used to divide patients into subgroups with high or low symptom levels.
RESULTS: Forty-one percent of the 344 patients enrolled had a high overall symptom burden. The most prevalent moderate/severe symptoms were fatigue (47%), pain (42%), numbness (38%), and bone aches (32%). For non-Hispanic whites, the IL1β -511 CC genotype was associated with a high overall symptom burden (odds ratio [OR], 2.35; 95% confidence interval [CI], 1.25-4.72; P = .004), whereas the IL6 -174 GG genotype predicted less moderate/severe fatigue (OR, 0.53; 95% CI, 0.29-0.88; P = .013). For other patients, the IL6 -174 GG genotype predicted moderate/severe pain (OR, 3.36; 95% CI, 1.23-13.64; P = .010).
CONCLUSIONS: These results support growing evidence showing that inflammation is associated with cancer-related symptoms, and they suggest that racial/ethnic factors contribute to this association.

Pawlyn C, Melchor L, Murison A, et al.
Coexistent hyperdiploidy does not abrogate poor prognosis in myeloma with adverse cytogenetics and may precede IGH translocations.
Blood. 2015; 125(5):831-40 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
The acquisition of the cytogenetic abnormalities hyperdiploidy or translocations into the immunoglobulin gene loci are considered as initiating events in the pathogenesis of myeloma and were often assumed to be mutually exclusive. These lesions have clinical significance; hyperdiploidy or the presence of the t(11;14) translocation is associated with a favorable outcome, whereas t(4;14), t(14;16), and t(14;20) are unfavorable. Poor outcomes are magnified when lesions occur in association with other high-risk features, del17p and +1q. Some patients have coexistence of both good and poor prognostic lesions, and there has been no consensus on their risk status. To address this, we have investigated their clinical impact using cases in the Myeloma IX study (ISRCTN68454111) and shown that the coexistence of hyperdiploidy or t(11;14) does not abrogate the poor prognosis associated with adverse molecular lesions, including translocations. We have also used single-cell analysis to study cases with coexistent translocations and hyperdiploidy to determine how these lesions cosegregate within the clonal substructure, and we have demonstrated that hyperdiploidy may precede IGH translocation in a proportion of patients. These findings have important clinical and biological implications, as we conclude patients with coexistence of adverse lesions and hyperdiploidy should be considered high risk and treated accordingly.

Dou A, Wang Z, Zhao J, et al.
Identification of therapeutic target genes with DNA microarray in multiple myeloma cell line treated by IKKβ/NF-κB inhibitor.
Acta Cir Bras. 2014; 29(11):696-702 [PubMed] Related Publications
PURPOSE: To explore the mechanism of resistance to IKKβ inhibitor in multiple myeloma (MM) cells and uncover novel therapeutic targets for MM.
METHODS: We downloaded the microarray data (GSE8476) from GEO (Gene Expression Omnibus) database. The data were derived from the human MM cells lines (L363 cells) treated with IKKβ inhibitor MLN120b (MLN) for eight, 12 and 24 hours. Furthermore, we applied the Search Tool for the Retrieval of Interacting Genes (STRING) and Expression Analysis Systematic Explorer (EASE) database to construct protein-protein interaction networks and identified over-represented pathway among DEGs (differentially expressed genes).
RESULTS: We obtained 108 DGEs in 8h vs. 12h group and 101 ones in 8h vs. 24h group. Most of DGEs were found to be involved in biological regulation. The significant pathways were Ig A pathway and the CAMs pathways. In addition, 24 common DGEs were found in the networks of the two groups such as ICAM 3 and SELL.
CONCLUSION: Intercellular adhesion molecule 3 and SELL may be potential targets in multiple myeloma treatment in the future.

Stewart MD, Ramani VC, Sanderson RD
Shed syndecan-1 translocates to the nucleus of cells delivering growth factors and inhibiting histone acetylation: a novel mechanism of tumor-host cross-talk.
J Biol Chem. 2015; 290(2):941-9 [PubMed] Article available free on PMC after 09/01/2016 Related Publications
The heparan sulfate proteoglycan syndecan-1 is proteolytically shed from the surface of multiple myeloma cells and is abundant in the bone marrow microenvironment where it promotes tumor growth, angiogenesis, and metastasis. In this study, we demonstrate for the first time that shed syndecan-1 present in the medium conditioned by tumor cells is taken up by bone marrow-derived stromal cells and transported to the nucleus. Translocation of shed syndecan-1 (sSDC1) to the nucleus was blocked by addition of exogenous heparin or heparan sulfate, pretreatment of conditioned medium with heparinase III, or growth of cells in sodium chlorate, indicating that sulfated heparan sulfate chains are required for nuclear translocation. Interestingly, cargo bound to sSDC1 heparan sulfate chains (i.e. hepatocyte growth factor) was transported to the nucleus along with sSDC1, and removal of heparan sulfate-bound cargo from sSDC1 abolished its translocation to the nucleus. Once in the nucleus, sSDC1 binds to the histone acetyltransferase enzyme p300, and histone acetyltransferase activity and histone acetylation are diminished. These findings reveal a novel function for shed syndecan-1 in mediating tumor-host cross-talk by shuttling growth factors to the nucleus and by altering histone acetylation in host cells. In addition, this work has broad implications beyond myeloma because shed syndecan-1 is present in high levels in many tumor types as well as in other disease states.

Zhu YX, Yin H, Bruins LA, et al.
RNA interference screening identifies lenalidomide sensitizers in multiple myeloma, including RSK2.
Blood. 2015; 125(3):483-91 [PubMed] Article available free on PMC after 09/01/2016 Related Publications
To identify molecular targets that modify sensitivity to lenalidomide, we measured proliferation in multiple myeloma (MM) cells transfected with 27 968 small interfering RNAs in the presence of increasing concentrations of drug and identified 63 genes that enhance activity of lenalidomide upon silencing. Ribosomal protein S6 kinase (RPS6KA3 or RSK2) was the most potent sensitizer. Other notable gene targets included 5 RAB family members, 3 potassium channel proteins, and 2 peroxisome family members. Single genes of interest included I-κ-B kinase-α (CHUK), and a phosphorylation dependent transcription factor (CREB1), which associate with RSK2 to regulate several signaling pathways. RSK2 knockdown induced cytotoxicity across a panel of MM cell lines and consistently increased sensitivity to lenalidomide. Accordingly, 3 small molecular inhibitors of RSK2 demonstrated synergy with lenalidomide cytotoxicity in MM cells even in the presence of stromal contact. Both RSK2 knockdown and small molecule inhibition downregulate interferon regulatory factor 4 and MYC, and provides an explanation for the synergy between lenalidomide and RSK2 inhibition. Interestingly, RSK2 inhibition also sensitized MM cells to bortezomib, melphalan, and dexamethasone, but did not downregulate Ikaros or influence lenalidomide-mediated downregulation of tumor necrosis factor-α or increase lenalidomide-induced IL-2 upregulation. In summary, inhibition of RSK2 may prove a broadly useful adjunct to MM therapy.

Paíno T, Paiva B, Sayagués JM, et al.
Phenotypic identification of subclones in multiple myeloma with different chemoresistant, cytogenetic and clonogenic potential.
Leukemia. 2015; 29(5):1186-94 [PubMed] Related Publications
Knowledge about clonal diversity and selection is critical to understand multiple myeloma (MM) pathogenesis, chemoresistance and progression. If targeted therapy becomes reality, identification and monitoring of intraclonal plasma cell (PC) heterogeneity would become increasingly demanded. Here we investigated the kinetics of intraclonal heterogeneity among 116 MM patients using 23-marker multidimensional flow cytometry (MFC) and principal component analysis, at diagnosis and during minimal residual disease (MRD) monitoring. Distinct phenotypic subclones were observed in 35/116 (30%) newly diagnosed MM patients. In 10/35 patients, persistent MRD was detected after 9 induction cycles, and longitudinal comparison of patient-paired diagnostic vs MRD samples unraveled phenotypic clonal tiding after therapy in half (5/10) of the patients. After demonstrating selection of distinct phenotypic subsets by therapeutic pressure, we investigated whether distinct fluorescence-activated cell-sorted PC subclones had different clonogenic and cytogenetic profiles. In half (5/10) of the patients analyzed, distinct phenotypic subclones showed different clonogenic potential when co-cultured with stromal cells, and in 6/11 cases distinct phenotypic subclones displayed unique cytogenetic profiles by interphase fluorescence in situ hybridization, including selective del(17p13). Collectively, we unravel potential therapeutic selection of preexisting diagnostic phenotypic subclones during MRD monitoring; because phenotypically distinct PCs may show different clonogenic and cytogenetic profiles, identification and follow-up of unique phenotypic-genetic myeloma PC subclones may become relevant for tailored therapy.

Cho SF, Chang YC, Chang CS, et al.
MALAT1 long non-coding RNA is overexpressed in multiple myeloma and may serve as a marker to predict disease progression.
BMC Cancer. 2014; 14:809 [PubMed] Article available free on PMC after 09/01/2016 Related Publications
BACKGROUND: The pathogenesis of multiple myeloma involves complex genetic and epigenetic events. This study aimed to investigate the role and clinical relevance of the long non-coding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in multiple myeloma.
METHODS: Bone marrow mononuclear cells were collected for analysis. The samples of multiple myeloma were taken from 45 patients at diagnosis, 61 post-treatment, and 18 who relapsed or had progression. Control samples were collected from 20 healthy individuals. Real-time quantitative reverse transcription polymerase chain reactions were performed to evaluate the expression of MALAT1. The clinical relevance of MALAT1 expression was also explored.
RESULTS: MALAT1 was overexpressed in the newly diagnosed patients compared with post-treatment patients (mean ∆CT: -5.54 ± 0.16 vs. -3.84 ± 0.09, 3.25-fold change; p < 0.001) and healthy individuals (mean ∆CT: -5.54 ± 0.16 vs. -3.95 ± 0.21, 3.01-fold change; p < 0.001). The expression of MALAT1 strongly correlated with disease status, and the magnitude of change in MALAT1 post-treatment had prognostic relevance. The patients with early progression had a significantly smaller change in MALAT1 after treatment (mean ∆CT change: 1.26 ± 1.06 vs. 2.09 ± 0.79, p = 0.011). A cut-off value of the change in MALAT1 (∆CT change: 1.5) was obtained, and the patients with a greater decrease in MALAT1 (difference in ∆CT >1.5) had significantly longer progression-free survival compared with the patients with a smaller MALAT1 change (24 months vs. 11 months; p = 0.001). For the post-treatment patients, the risk of early progression could be predicted using this cut-off value.
CONCLUSIONS: MALAT1 was overexpressed in patients with myeloma and may play a role in its pathogenesis. In addition, MALAT1 may serve as a molecular predictor of early progression.

Varga G, Mikala G, Andrikovics H, et al.
NFKB1 -94ins/delATTG polymorphism is a novel prognostic marker in first line-treated multiple myeloma.
Br J Haematol. 2015; 168(5):679-88 [PubMed] Related Publications
Nuclear factor kappa B (NFKB) plays an important role in multiple myeloma (MM), and bortezomib affects this pathway. We retrospectively analysed the effect of the NFKB1 -94ins/delATTG polymorphism on the survival of 295 MM patients treated at a single centre. The median progression-free survival (PFS) was 790 (659-921) d in patients with NFKB1 homozygous insertion genotype (I/I, n = 99) and 624 (515-733) d in deletion-carriers (I/D&D/D, n = 196, P = 0·013). In multivariate analysis, I/I carriers showed a favourable PFS compared to I/D&D/D with a hazard ratio of 0·622 (0·457-0·847), P = 0·003, in addition to international staging system (ISS) score, fluorescence in situ hybridization (FISH) risk score, age and bortezomib treatment. I/I patients benefited more from bortezomib treatment [PFS 902 (703-1101) and 580 (343-817), P = 0·008] than I/D&D/D patients [PFS 659 (487-831) and 488 (323-653), P = 0·531]; in addition the beneficial effect of low ISS score was not observed in the I/D&D/D group [PFS 639 (454-824) and 650 (458-842), P = 0·226], while it was clear in I/I patients [PFS 1140 (803-1477) and 580 (408-752), P < 0·001]. We conclude that homozygous carriers of the insertion allele of the NFKB1 -94ins/delATTG polymorphism have a better prognosis and probably benefit more from bortezomib treatment than MM patients carrying the deletion allele.

Kortüm KM, Langer C, Monge J, et al.
Targeted sequencing using a 47 gene multiple myeloma mutation panel (M(3) P) in -17p high risk disease.
Br J Haematol. 2015; 168(4):507-10 [PubMed] Article available free on PMC after 09/01/2016 Related Publications
We constructed a multiple myeloma (MM)-specific gene panel for targeted sequencing and investigated 72 untreated high-risk (del17p) MM patients. Mutations were identified in 78% of the patients. While the majority of studied genes were mutated at similar frequency to published literature, the prevalence of TP53 mutation was increased (28%) and no mutations were found in FAM46C. This study provides a comprehensive insight into the mutational landscape of del17p high-risk MM. Additionally, our work demonstrates the practical use of a customized sequencing panel, as an easy, cheap and fast approach to characterize the mutational profile of MM.

Boyle EM, Proszek PZ, Kaiser MF, et al.
A molecular diagnostic approach able to detect the recurrent genetic prognostic factors typical of presenting myeloma.
Genes Chromosomes Cancer. 2015; 54(2):91-8 [PubMed] Article available free on PMC after 09/01/2016 Related Publications
Risk stratification in myeloma requires an accurate assessment of the presence of a range of molecular abnormalities including the differing IGH translocations and the recurrent copy number abnormalities that can impact clinical behavior. Currently, interphase fluorescence in situ hybridization is used to detect these abnormalities. High failure rates, slow turnaround, cost, and labor intensiveness make it difficult and expensive to use in routine clinical practice. Multiplex ligation-dependent probe amplification (MLPA), a molecular approach based on a multiplex polymerase chain reaction method, offers an alternative for the assessment of copy number changes present in the myeloma genome. Here, we provide evidence showing that MLPA is a powerful tool for the efficient detection of copy number abnormalities and when combined with expression assays, MLPA can detect all of the prognostically relevant molecular events which characterize presenting myeloma. This approach opens the way for a molecular diagnostic strategy that is efficient, high throughput, and cost effective.

Xu H, Liu C, Zhang Y, et al.
Let-7b-5p regulates proliferation and apoptosis in multiple myeloma by targeting IGF1R.
Acta Biochim Biophys Sin (Shanghai). 2014; 46(11):965-72 [PubMed] Related Publications
Multiple myeloma (MM) is the most common cause of death from hematological malignancy worldwide, and recent studies have revealed that let-7b-5p can play an inhibitory role in tumorigenesis. However, the role of let-7b-5p in MM still remains unclear. The aim of this study was to elucidate the molecular mechanisms by which let-7b-5p acts as a tumor suppressor in MM. Here, quantitative real-time polymerase chain reaction results showed that the expression of let-7b-5p was remarkably reduced in MM tissues and MM cell lines (RPMI-8226 and U266 cells). Furthermore, over-expression of let-7b-5p significantly suppressed RPMI-8226 cell proliferation and induced S/G2 cell cycle arrest and apoptosis. Luciferase reporter assay results demonstrated that insulin-like growth factor receptor 1 (IGF1R) was negatively regulated by let-7b-5p at the post-transcriptional level. The mRNA and protein levels of IGF1R in RPMI-8226 cells were down-regulated by let-7b-5p. Furthermore, the cell phenotype altered by let-7b-5p inhibitor can be rescued by IGF1R silencing (si-IGF1R). Taken together, our results demonstrated that let-7b-5p functions as a tumor suppressor in MM, suggesting that let-7b-5p may be a potential therapeutic target for MM.

Chinen Y, Kuroda J, Shimura Y, et al.
Phosphoinositide protein kinase PDPK1 is a crucial cell signaling mediator in multiple myeloma.
Cancer Res. 2014; 74(24):7418-29 [PubMed] Related Publications
Multiple myeloma is a cytogenetically/molecularly heterogeneous hematologic malignancy that remains mostly incurable, and the identification of a universal and relevant therapeutic target molecule is essential for the further development of therapeutic strategy. Herein, we identified that 3-phosphoinositide-dependent protein kinase 1 (PDPK1), a serine threonine kinase, is expressed and active in all eleven multiple myeloma-derived cell lines examined regardless of the type of cytogenetic abnormality, the mutation state of RAS and FGFR3 genes, or the activation state of ERK and AKT. Our results revealed that PDPK1 is a pivotal regulator of molecules that are essential for myelomagenesis, such as RSK2, AKT, c-MYC, IRF4, or cyclin Ds, and that PDPK1 inhibition caused the growth inhibition and the induction of apoptosis with the activation of BIM and BAD, and augmented the in vitro cytotoxic effects of antimyeloma agents in myeloma cells. In the clinical setting, PDPK1 was active in myeloma cells of approximately 90% of symptomatic patients at diagnosis, and the smaller population of patients with multiple myeloma exhibiting myeloma cells without active PDPK1 showed a significantly less frequent proportion of the disease stage III by the International Staging System and a significantly more favorable prognosis, including the longer overall survival period and the longer progression-free survival period by bortezomib treatment, than patients with active PDPK1, suggesting that PDPK1 activation accelerates the disease progression and the resistance to treatment in multiple myeloma. Our study demonstrates that PDPK1 is a potent and a universally targetable signaling mediator in multiple myeloma regardless of the types of cytogenetic/molecular profiles.

Garcia-Gomez A, De Las Rivas J, Ocio EM, et al.
Transcriptomic profile induced in bone marrow mesenchymal stromal cells after interaction with multiple myeloma cells: implications in myeloma progression and myeloma bone disease.
Oncotarget. 2014; 5(18):8284-305 [PubMed] Article available free on PMC after 09/01/2016 Related Publications
Despite evidence about the implication of the bone marrow (BM) stromal microenvironment in multiple myeloma (MM) cell growth and survival, little is known about the effects of myelomatous cells on BM stromal cells. Mesenchymal stromal cells (MSCs) from healthy donors (dMSCs) or myeloma patients (pMSCs) were co-cultured with the myeloma cell line MM.1S, and the transcriptomic profile of MSCs induced by this interaction was analyzed. Deregulated genes after co-culture common to both d/pMSCs revealed functional involvement in tumor microenvironment cross-talk, myeloma growth induction and drug resistance, angiogenesis and signals for osteoclast activation and osteoblast inhibition. Additional genes induced by co-culture were exclusively deregulated in pMSCs and predominantly associated to RNA processing, the ubiquitine-proteasome pathway, cell cycle regulation, cellular stress and non-canonical Wnt signaling. The upregulated expression of five genes after co-culture (CXCL1, CXCL5 and CXCL6 in d/pMSCs, and Neuregulin 3 and Norrie disease protein exclusively in pMSCs) was confirmed, and functional in vitro assays revealed putative roles in MM pathophysiology. The transcriptomic profile of pMSCs co-cultured with myeloma cells may better reflect that of MSCs in the BM of myeloma patients, and provides new molecular insights to the contribution of these cells to MM pathophysiology and to myeloma bone disease.

Rashid NU, Sperling AS, Bolli N, et al.
Differential and limited expression of mutant alleles in multiple myeloma.
Blood. 2014; 124(20):3110-7 [PubMed] Article available free on PMC after 13/11/2015 Related Publications
Recent work has delineated mutational profiles in multiple myeloma and reported a median of 52 mutations per patient, as well as a set of commonly mutated genes across multiple patients. In this study, we have used deep sequencing of RNA from a subset of these patients to evaluate the proportion of expressed mutations. We find that the majority of previously identified mutations occur within genes with very low or no detectable expression. On average, 27% (range, 11% to 47%) of mutated alleles are found to be expressed, and among mutated genes that are expressed, there often is allele-specific expression where either the mutant or wild-type allele is suppressed. Even in the absence of an overall change in gene expression, the presence of differential allelic expression within malignant cells highlights the important contribution of RNA-sequencing in identifying clinically significant mutational changes relevant to our understanding of myeloma biology and also for therapeutic applications.

Jagannathan S, Vad N, Vallabhapurapu S, et al.
MiR-29b replacement inhibits proteasomes and disrupts aggresome+autophagosome formation to enhance the antimyeloma benefit of bortezomib.
Leukemia. 2015; 29(3):727-38 [PubMed] Article available free on PMC after 13/11/2015 Related Publications
Evading apoptosis is a cancer hallmark that remains a serious obstacle in current treatment approaches. Although proteasome inhibitors (PIs) have transformed management of multiple myeloma (MM), drug resistance emerges through induction of the aggresome+autophagy pathway as a compensatory protein clearance mechanism. Genome-wide profiling identified microRNAs (miRs) differentially expressed in bortezomib-resistant myeloma cells compared with drug-naive cells. The effect of individual miRs on proteasomal degradation of short-lived fluorescent reporter proteins was then determined in live cells. MiR-29b was significantly reduced in bortezomib-resistant cells as well as in cells resistant to second-generation PIs carfilzomib and ixazomib. Luciferase reporter assays demonstrated that miR-29b targeted PSME4 that encodes the proteasome activator PA200. Synthetically engineered miR-29b replacements impaired the growth of myeloma cells, patient tumor cells and xenotransplants. MiR-29b replacements also decreased PA200 association with proteasomes, reduced the proteasome's peptidase activity and inhibited ornithine decarboxylase turnover, a proteasome substrate degraded through ubiquitin-independent mechanisms. Immunofluorescence studies revealed that miR-29b replacements enhanced the bortezomib-induced accumulation of ubiquitinated proteins but did not reveal aggresome or autophagosome formation. Taken together, our study identifies miR-29b replacements as the first-in-class miR-based PIs that also disrupt the autophagy pathway and highlight their potential to synergistically enhance the antimyeloma effect of bortezomib.

Sadahira K, Sagawa M, Nakazato T, et al.
Gossypol induces apoptosis in multiple myeloma cells by inhibition of interleukin-6 signaling and Bcl-2/Mcl-1 pathway.
Int J Oncol. 2014; 45(6):2278-86 [PubMed] Article available free on PMC after 13/11/2015 Related Publications
Multiple myeloma (MM) is a clonal plasma cell disorder affecting the immune system with various systemic symptoms. MM remains incurable even with high dose chemotherapy using conventional drugs, thus necessitating development of novel therapeutic strategies. Gossypol (Gos) is a natural polyphenolic compound extracted from cotton plants, and has been shown to possess anti-neoplastic activity against various tumors. Recent studies have shown that Gos is an inhibitor for Bcl-2 or Bcl-XL acting as BH3 mimetics that interfere interaction between pro-apoptotic BH3-only proteins and Bcl-2/Bcl-XL. Since most of the patients with MM overexpress Bcl-2 protein, we considered Gos might be a promising therapeutic agent for MM. We herein show that Gos efficiently induced apoptosis and inhibited proliferation of the OPM2 MM cell line, in a dose- and time-dependent manner. Gos induced activation of caspase-3 and cytochrome c release from mitochondria, showing mitochondrial dysfunction pathway is operational during apoptosis. Further investigation revealed that phosphorylation of Bcl-2 at serine-70 was attenuated by Gos treatment, while protein levels were not affected. In addition, Mcl-1 was downregulated by Gos. Interestingly, phosphorylation of JAK2, STAT3, ERK1/2 and p38MAPK was inhibited by Gos-treatment, indicating that Gos globally suppressed interleukin-6 (IL-6) signals. Moreover, JAK2 inhibition mimicked the effect of Gos in OPM2 cells including Bcl-2 dephosphorylation and Mcl-1 downregulation. These results demonstrated that Gos induces apoptosis in MM cells not only through displacing BH3-only proteins from Bcl-2, but also through inhibiting IL-6 signaling, which leads to Bcl-2 dephosphorylation and Mcl-1 downregulation.

Hao M, Zang M, Wendlandt E, et al.
Low serum miR-19a expression as a novel poor prognostic indicator in multiple myeloma.
Int J Cancer. 2015; 136(8):1835-44 [PubMed] Article available free on PMC after 15/04/2016 Related Publications
Multiple myeloma (MM) is the second most common hematologic malignancy characterized by the clonal expansion of plasma cells. Despite continuing advances, novel biomarkers are needed for diagnosis and prognosis of MM. In our study, we characterized the diagnostic and prognostic potential of circulating microRNAs (miRNAs) in MM. Serum miRNA levels were analyzed in 108 newly diagnosed symptomatic MM patients and 56 healthy donors (HDs). Our analysis identified 95 dysregulated miRNAs in newly diagnosed MM patients. Of the 95 dysregulated miRNAs, dysregulation of miR-19a, miR-92a, miR-214-3p, miR-135b-5p, miR-4254, miR-3658 and miR-33b was confirmed by quantitative reverse transcription PCR (RT-qPCR). Receiver operating characteristic analysis revealed that a combination of miR-19a and miR-4254 can distinguish MM from HD with a sensitivity of 91.7% and specificity of 90.5%. Decreased expression of miR-19a was positively correlated with international staging system advancement, del(13q14) and 1q21 amplification. Furthermore, downregulation of miR-19a resulted in significantly decreased progression-free survival (PFS) and overall survival (OS). Our analysis indicated that the poor prognostic correlation of miR-19a expression was independent of genetic abnormalities in MM. Multivariate analysis revealed that miR-19a was a significant predictor of shortened PFS and OS. Interestingly, although miR-19a levels portend a poor prognosis, patients with low miR-19a levels had an improved response to bortezomib compared to those with high miR-19a profile. Patients with downregulated miR-19a experienced a significantly extended survival upon bortezomib-based therapy. These data demonstrate that the expression patterns of serum microRNAs are altered in MM, and miR-19a levels are a valuable prognostic marker to identify high-risk MM.

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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