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.

  • Recurrence
  • Multiple Myeloma
  • MicroRNAs
  • Bone Marrow
  • Smoothened Receptor
  • drug, Bortezomib (Velcade)
  • Disease-Free Survival
  • Staging
  • RNA-Binding Proteins
  • Cancer Gene Expression Regulation
  • CCND2
  • Antineoplastic Agents
  • Precision Medicine
  • Genetic Predisposition
  • Mutation
  • Phosphatidylinositol 3-Kinases
  • SDC1
  • Case-Control Studies
  • MAF
  • CIC
  • DKK1
  • Genomics
  • STAT3 Transcription Factor
  • Epigenetics
  • BIRC3
  • Survival Rate
  • High-Throughput Nucleotide Sequencing
  • BCL9
  • NFKB1
  • Transcriptome
  • Chromosome Aberrations
  • Gene Expression Profiling
  • FISH
  • Drug Resistance
  • Reproducibility of Results
  • Cell Proliferation
  • AR
  • Genotype
  • Gene Expression
  • Plasma Cells
  • Disease Progression
  • Biomarkers, Tumor
  • Cell Survival
  • Apoptosis
  • Th2 Cells
  • Long Noncoding RNA
  • Outcome Assessment (Health Care)
  • Proto-Oncogene Proteins
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (92)

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
AR Xq12 KD, AIS, AR8, TFM, DHTR, SBMA, HYSP1, NR3C4, SMAX1, HUMARA -AR and Multiple Myeloma
FGFR3 4p16.3 ACH, CEK2, JTK4, CD333, HSFGFR3EX -FGFR3 and Multiple Myeloma
MAF 16q23.2 CCA4, AYGRP, c-MAF, CTRCT21 -MAF and Multiple Myeloma
CD19 16p11.2 B4, CVID3 -CD19 and Multiple Myeloma
TNFRSF11A 18q21.33 FEO, OFE, ODFR, OSTS, PDB2, RANK, CD265, OPTB7, TRANCER, LOH18CR1 -TNFRSF11A and Multiple Myeloma
TNFRSF11B 8q24.12 OPG, TR1, OCIF, PDB5 -TNFRSF11B and Multiple Myeloma
SDC1 2p24.1 SDC, CD138, SYND1, syndecan -SDC1 and Multiple Myeloma
NSD2 4p16.3 WHS, TRX5, KMT3F, KMT3G, MMSET, WHSC1, REIIBP -WHSC1 and Multiple Myeloma
DKK1 10q21.1 SK, DKK-1 -DKK1 and Multiple Myeloma
XBP1 22q12.1 XBP2, TREB5, XBP-1, TREB-5 -XBP1 and Multiple Myeloma
CKS1B 1q21.3 CKS1, ckshs1, PNAS-16, PNAS-18 -CKS1B and Multiple Myeloma
CCND2 12p13.32 MPPH3, KIAK0002 -CCND2 and Multiple Myeloma
CCND3 6p21.1 -CCND3 and Multiple Myeloma
IGL 22q11.22 IGL@, IGLC6 -IGL and Multiple Myeloma
TNFSF11 13q14.11 ODF, OPGL, sOdf, CD254, OPTB2, RANKL, TNLG6B, TRANCE, hRANKL2 -TNFSF11 and Multiple Myeloma
CCL3 17q12 MIP1A, SCYA3, G0S19-1, LD78ALPHA, MIP-1-alpha -CCL3 and Multiple Myeloma
NFKB1 4q24 p50, KBF1, p105, EBP-1, CVID12, NF-kB1, NFKB-p50, NFkappaB, NF-kappaB, NFKB-p105, NF-kappa-B -NFKB1 and Multiple Myeloma
TENT5C 1p12 FAM46C -FAM46C and Multiple Myeloma
CD27 12p13.31 T14, S152, Tp55, TNFRSF7, S152. LPFS2 -CD27 and Multiple Myeloma
TRAF3 14q32.32 CAP1, LAP1, CAP-1, CRAF1, IIAE5, CD40bp -TRAF3 and Multiple Myeloma
IGK 2p12 IGK@ -IGK and Multiple Myeloma
PRDM1 6q21 BLIMP1, PRDI-BF1 -PRDM1 and Multiple Myeloma
IRF4 6p25.3 MUM1, LSIRF, SHEP8, NF-EM5 Translocation
-t(6;14)(p25;q32) in Myeloma
CIC 19q13.2 -CIC and Multiple Myeloma
TNFRSF17 16p13.13 BCM, BCMA, CD269, TNFRSF13A -TNFRSF17 and Multiple Myeloma
B2M 15q21.1 IMD43 -B2M and Multiple Myeloma
AURKA 20q13.2 AIK, ARK1, AURA, BTAK, STK6, STK7, STK15, PPP1R47 -AURKA and Multiple Myeloma
MUM1 19p13.3 MUM-1, EXPAND1, HSPC211 -MUM1 and Multiple Myeloma
TNFSF13B 13q33.3 DTL, BAFF, BLYS, CD257, TALL1, THANK, ZTNF4, TALL-1, TNLG7A, TNFSF20 -TNFSF13B and Multiple Myeloma
THRA 17q21.1 AR7, EAR7, ERBA, CHNG6, ERBA1, NR1A1, THRA1, THRA2, ERB-T-1, c-ERBA-1 -THRA and Multiple Myeloma
IL6ST 5q11.2 CD130, GP130, CDW130, IL-6RB -IL6ST and Multiple Myeloma
NFKB2 10q24.32 p52, p100, H2TF1, LYT10, CVID10, LYT-10, NF-kB2, p49/p100 -NFKB2 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
BIRC3 11q22.2 AIP1, API2, MIHC, CIAP2, HAIP1, HIAP1, MALT2, RNF49, c-IAP2 -BIRC3 and Multiple Myeloma
SCFV 14 -SCFV and Multiple Myeloma
BCL9 1q21.2 LGS -BCL9 and Multiple Myeloma
FRZB 2q32.1 FRE, OS1, FZRB, hFIZ, FRITZ, FRP-3, FRZB1, SFRP3, SRFP3, FRZB-1, FRZB-PEN -FRZB and Multiple Myeloma
GALM 2p22.1 GLAT, IBD1, BLOCK25, HEL-S-63p -GALM and Multiple Myeloma
PIM2 Xp11.23 -PIM2 and Multiple Myeloma
CD52 1p36.11 HE5, CDW52, EDDM5 -CD52 and Multiple Myeloma
HAS1 19q13.41 HAS -HAS1 and Multiple Myeloma
CDR2 16p12.2 Yo, CDR62 -CDR2 and Multiple Myeloma
CYP2C8 10q23.33 CPC8, CYPIIC8, MP-12/MP-20 -CYP2C8 and Multiple Myeloma
ITGA4 2q31.3 IA4, CD49D -ITGA4 and Multiple Myeloma
TACC3 4p16.3 ERIC1, ERIC-1 -TACC3 and Multiple Myeloma
CD58 1p13.1 ag3, LFA3, LFA-3 -CD58 and Multiple Myeloma
MBL2 10q21.1 MBL, MBP, MBP1, MBPD, MBL2D, MBP-C, COLEC1, HSMBPC -MBL2 and Multiple Myeloma
CD81 11p15.5 S5.7, CVID6, TAPA1, TSPAN28 -CD81 and Multiple Myeloma
IL6R 1q21.3 IL6Q, gp80, CD126, IL6RA, IL6RQ, IL-6RA, IL-6R-1 -IL6R and Multiple Myeloma
FAS 10q23.31 APT1, CD95, FAS1, APO-1, FASTM, ALPS1A, TNFRSF6 -FAS and Multiple Myeloma
BIRC2 11q22.2 API1, MIHB, HIAP2, RNF48, cIAP1, Hiap-2, c-IAP1 -BIRC2 and Multiple Myeloma
SLC7A5 16q24.2 E16, CD98, LAT1, 4F2LC, MPE16, D16S469E -SLC7A5 and Multiple Myeloma
PDCD5 19q13.11 TFAR19 -PDCD5 and Multiple Myeloma
CD200 3q13.2 MRC, MOX1, MOX2, OX-2 -CD200 and Multiple Myeloma
P2RX7 12q24 P2X7 -P2RX7 and Multiple Myeloma
JAG2 14q32.33 HJ2, SER2 -JAG2 and Multiple Myeloma
DLK1 14q32.2 DLK, FA1, ZOG, pG2, DLK-1, PREF1, Delta1, Pref-1 -DLK1 and Multiple Myeloma
TLR1 4p14 TIL, CD281, rsc786, TIL. LPRS5 -TLR1 and Multiple Myeloma
FCGR2A 1q23.3 CD32, FCG2, FcGR, CD32A, CDw32, FCGR2, IGFR2, FCGR2A1 -FCGR2A and Multiple Myeloma
SLAMF1 1q23.3 SLAM, CD150, CDw150 -SLAMF1 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
PCDH10 4q28.3 PCDH19, OL-PCDH -PCDH10 and Multiple Myeloma
MIRLET7E 19q13.41 LET7E, let-7e, MIRNLET7E, hsa-let-7e -None and Multiple Myeloma
BACH2 6q15 BTBD25 -BACH2 and Multiple Myeloma
IL21 4q27 Za11, IL-21, CVID11 -IL21 and Multiple Myeloma
TNFSF13 17p13.1 APRIL, CD256, TALL2, ZTNF2, TALL-2, TNLG7B, TRDL-1, UNQ383/PRO715 -TNFSF13 and Multiple Myeloma
RHOBTB2 8p21.3 DBC2 -RHOBTB2 and Multiple Myeloma
LTB 6p21.33 p33, TNFC, TNFSF3, TNLG1C -LTB and Multiple Myeloma
POU2AF1 11q23.1 BOB1, OBF1, OCAB, OBF-1 -POU2AF1 and Multiple Myeloma
PIAS3 1q21.1 ZMIZ5 -PIAS3 and Multiple Myeloma
MAP3K8 10p11.23 COT, EST, ESTF, TPL2, AURA2, MEKK8, Tpl-2, c-COT -MAP3K8 and Multiple Myeloma
BAGE 21p11.1 BAGE1, CT2.1 -BAGE and Multiple Myeloma
HAS3 16q22.1 -HAS3 and Multiple Myeloma
TLR7 Xp22.2 TLR7-like -TLR7 and Multiple Myeloma
NFATC1 18q23 NFAT2, NFATc, NF-ATC, NF-ATc1.2 -NFATC1 and Multiple Myeloma
TYRO3 15q15.1 BYK, Dtk, RSE, Rek, Sky, Tif, Etk-2 -TYRO3 and Multiple Myeloma
CD1D 1q23.1 R3, CD1A, R3G1 -CD1D and Multiple Myeloma
KL 13q13.1 -KL and Multiple Myeloma
SRPX Xp11.4 DRS, ETX1, SRPX1, HEL-S-83p -SRPX and Multiple Myeloma
TRIM13 13q14.2 CAR, LEU5, RFP2, DLEU5, RNF77 -TRIM13 and Multiple Myeloma
RNF217-AS1 6q22.31 STL -STL and Multiple Myeloma
ADAMTS9 3p14.1 -ADAMTS9 and Multiple Myeloma
MIR106B 7q22.1 MIRN106B, mir-106b -MIR106B and Multiple Myeloma
ITGAL 16p11.2 CD11A, LFA-1, LFA1A -ITGAL and Multiple Myeloma
ZNF331 19q13.42 RITA, ZNF361, ZNF463 -ZNF331 and Multiple Myeloma
CD47 3q13.1-q13.2 IAP, OA3, MER6 -CD47 and Multiple Myeloma
IFNA2 9p21.3 IFNA, INFA2, IFNA2B, IFN-alphaA -IFNA2 and Multiple Myeloma
IFNA7 9p21.3 IFNA-J, IFN-alphaJ -IFNA7 and Multiple Myeloma
IFNA17 9p21.3 IFNA, INFA, LEIF2C1, IFN-alphaI -IFNA17 and Multiple Myeloma
MAFB 20q12 KRML, MCTO, DURS3 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 P, Xia T, Ling Y, Chen B
MiRNAs with prognostic significance in multiple myeloma: A systemic review and meta-analysis.
Medicine (Baltimore). 2019; 98(33):e16711 [PubMed] Related Publications
BACKGROUND: Multiple myeloma (MM) is a clonal plasma cell malignancy associated with hypercalcemia, bone lesions, and renal failure. The prognostic significance of the mutation of miRNAs, one kind of small noncoding RNA molecules that can modulate gene expression, should be confirmed in non-Hodgkin lymphomas (NHL). This study aimed to identify the prognostic value of miRNAs in patients with MM.
METHODS: A meta-analysis was performed to estimate the pooled hazard ratios and their corresponding 95% confidence intervals for the associations between levels of miRNA expression (predictive factors) and outcomes in patients with MM. We systematically searched the PubMed, Web of Science, and China National Knowledge Infrastructure databases (final search conducted January 1, 2018) to identify eligible studies. Eligible studies were included by certain inclusion and exclusion criteria, whose quality was assessed by Newcastle-Ottawa Scale.
RESULTS: After performing the literature search and review, 10 relevant studies, including 1214 cases, were identified. The results of our meta-analysis revealed that upregulated miR-92a level and downregulated miR-16, miR-25, miR-744, miR-15a, let-7e, and miR-19b expression were associated with poor prognosis in MM.
CONCLUSIONS: This study identified miRNAs could serve as potential prognostic biomarkers in MM. Given the limited research available, the clinical application of these findings has yet to be verified.

Murase T, Ri M, Narita T, et al.
Immunohistochemistry for identification of CCND1, NSD2, and MAF gene rearrangements in plasma cell myeloma.
Cancer Sci. 2019; 110(8):2600-2606 [PubMed] Free Access to Full Article Related Publications
The t(11;14)/CCND1-IGH, t(4;14)/NSD2(MMSET)-IGH, and t(14;16)/IGH-MAF gene rearrangements detected by fluorescence in situ hybridization (FISH) are used for risk stratification in patients with multiple myeloma (MM). Compared with conventional FISH techniques using fresh cells, immunohistochemistry (IHC) is much more cost- and time-efficient, and can be readily applied to routinely prepared formalin-fixed, paraffin-embedded (FFPE) materials. In this study, we performed tissue FISH and IHC employing FFPE specimens, and examined the usefulness of IHC as a tool for detecting CCND1, NSD2, and MAF gene rearrangements. CD138 signals were used to identify plasma cells in tissue FISH and IHC analyses. With cohort 1 (n = 70), we performed tissue FISH and subsequently IHC, and determined IHC cut-off points. In this cohort, the sensitivity and specificity for the 3 molecules were ≥.90 and ≥.96, respectively. With cohort 2, using MM cases with an unknown gene status (n = 120), we performed IHC, and the gene status was estimated using the cut-off points determined with cohort 1. The subsequent FISH analysis showed that the sensitivity and specificity for the 3 molecules were ≥.92 and ≥.98, respectively. CCND1, NSD2, and MAF gene rearrangements were estimated accurately by IHC, suggesting that conventional FISH assays can be replaced by IHC.

Ai L, Mu S, Sun C, et al.
Myeloid-derived suppressor cells endow stem-like qualities to multiple myeloma cells by inducing piRNA-823 expression and DNMT3B activation.
Mol Cancer. 2019; 18(1):88 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Myeloid-derived suppressor cells (MDSCs) and cancer stem cells (CSCs) are two important cellular components in the tumor microenvironment, which may modify the cancer phenotype and affect patient survival. However, the crosstalk between MDSCs and multiple myeloma stem cells (MMSCs) are relatively poorly understood.
METHODS: The frequencies of granulocytic-MDSCs (G-MDSCs) in MM patients were detected by flow cytometry and their association with the disease stage and patient survival were analyzed. RT-PCR, flow cytometry, western blot and sphere formation assays were performed to investigate the effects of G-MDSCs, piRNA-823 and DNA methylation on the maintenance of stemness in MM. Then a subcutaneous tumor mouse model was constructed to analyze tumor growth and angiogenesis after G-MDSCs induction and/or piRNA-823 knockdown in MM cells.
RESULTS: Our clinical dataset validated the association between high G-MDSCs levels and poor overall survival in MM patients. In addition, for the first time we showed that G-MDSCs enhanced the side population, sphere formation and expression of CSCs core genes in MM cells. Moreover, the mechanism study showed that G-MDSCs triggered piRNA-823 expression, which then promoted DNA methylation and increased the tumorigenic potential of MM cells. Furthermore, silencing of piRNA-823 in MM cells reduced the stemness of MMSCs maintained by G-MDSCs, resulting in decreased tumor burden and angiogenesis in vivo.
CONCLUSION: Altogether, these data established a cellular, molecular, and clinical network among G-MDSCs, piRNA-823, DNA methylation and CSCs core genes, suggesting a new anti-cancer strategy targeting both G-MDSCs and CSCs in MM microenvironment.

Nishio Y, Sakai H, Saiki Y, et al.
Light-chain plasma cell myeloma caused by 14q32/IGH translocation and loss of the other allele.
Int J Hematol. 2019; 109(5):572-577 [PubMed] Related Publications
Light-chain plasma cell myeloma (LC-PCM) is a PCM subtype in which only immunoglobulin light-chain is secreted. However, the absence of immunoglobulin heavy-chain (IGH) production in this condition has not been fully elucidated. To address this issue, we retrospectively analyzed patients at our center with LC-PCM and found a group who had only split signals of IGH gene derived from 14q32/IGH translocations by fluorescence in situ hybridization (FISH). Six patients were identified with only split signals of the IGH gene derived from 14q32/IGH translocations. Five of these patients were newly diagnosed, while one had IgG-λ PCM at presentation, which transformed to λ LC-PCM after treatment. The translocation partners were identified in four patients: two cases of (11;14)(q13;q32) and two cases of (4;14)(p16;q32). The development of LC-PCM appears to be explained by the application of allelic exclusion in these patients, such that 14q32/IGH translocation in one allele contributes to the pathogenesis of PCM and the subsequent loss of the other allele is responsible for the loss of IGH production. These findings suggest that a FISH pattern of IGH with "split and loss" may constitute a unique subgroup of LC-PCM.

Yuan J, Su Z, Gu W, et al.
MiR-19b and miR-20a suppress apoptosis, promote proliferation and induce tumorigenicity of multiple myeloma cells by targeting PTEN.
Cancer Biomark. 2019; 24(3):279-289 [PubMed] Related Publications
Multiple myeloma (MM) is a common hematological malignancy that is often associated with osteolytic lesions, anemia and renal impairment. Deregulation of miRNA has been implicated in the pathogenesis of MM. It was found in our study that miR-19b and miR-20a as members of crucial oncogene miR-17-92 cluster were differentially expressed between patients with MM and normal controls by genechip microarray, and this result was further confirmed in sera of patients with MM by qRT-PCR. The functional effect of miR-19b/20a was analyzed and results showed that miR-19b/20a promoted cell proliferation and migration, inhibited cell apoptosis and altered cell cycle in MM cells. PTEN protein expression was reduced after transfection of miR-19b/20a, suggesting that PTEN was a direct target of miR-19b/20a. In addition, over-expression of miR-19b/20a reversed the anti-proliferation and pro-apoptosis effect of PTEN in MM cells. Finally, our in vivo experiment demonstrated that lentivirus-mediated delivery of miR-20a promoted tumor growth in murine xenograft model of MM, which provide evidence that miR-20a inhibitor exerts therapeutic activity in preclinical models and supports a framework for the development of miR-19b/20a-based treatment strategies for MM patients.

Legües ME, Morales P, Valenzuela M, et al.
[High risk cytogenetic abnormalities in patients with multiple myeloma].
Rev Med Chil. 2019; 147(1):61-64 [PubMed] Related Publications
BACKGROUND: Cytogenetic abnormalities observed in the bone marrow of patients with multiple myeloma (MM) are an important prognostic factor for risk stratification.
AIM: To investigate karyotype characteristics and frequency of the high-risk cytogenetic abnormalities t(4;14), t(14;16) and del(17p) in Chilean patients with MM.
MATERIAL AND METHODS: We studied 30 patients with MM by conventional cytogenetics (CC) and fluorescent in situ hybridization of plasma cells selected using cytoplasmic immunoglobulin staining (cIg-FISH).
RESULTS: Overall, the two techniques in combination allowed us to identify clonal genetic abnormalities in 47% of patients. The t(4;14) abnormality was observed in 19% of patients, del(17p) was observed in 10% of patients, and t(14;16) was not detected.
CONCLUSIONS: Our results showed frequencies of high-risk abnormalities similar to those reported abroad. Cytogenetic studies should be performed routinely for all MM patients at the moment of diagnosis.

Mendoza MG, Valladares X, Roa M, et al.
[Primary plasma cell leukemia. Report of five cases].
Rev Med Chil. 2019; 147(1):18-23 [PubMed] Related Publications
BACKGROUND: Primary plasma cell leukemia (pPCL) is uncommon, aggressive and has a different biology than multiple myeloma (MM).
AIM: To report the features of patients with pPCL.
MATERIAL AND METHODS: Review of databases of the Hematology Department and the Hematology laboratory.
RESULTS: Of 178 patients with monoclonal gammopathies, five (2.8%) patients aged 33 to 64 years (three females) had a pPCL. The mean hemoglobin was 7.3 g/dL, the mean white blood cell count was 52,500/mm3, with 58% plasma cells, and the mean platelet count was 83,600/mm3. The mean bone marrow infiltration was 89%, LDH was 2,003 IU/L, serum calcium was 13 mg/dL, and creatinine 1.5 mg/dL. Two patients had bone lesions. Three were IgG, one IgA lambda and one lambda light chain. CD20 was positive in one, CD56 was negative in all and CD117 was negative in 3 cases. By conventional cytogenetic analysis, two had a complex karyotype. By Fluorescence in situ Hybridization, one was positive for TP53 and another for t (11; 14). One patient did not receive any treatment, three patients received VTD PACE and one CTD. None underwent transplant. Three patients are alive. The mean survival was 14 months.
CONCLUSIONS: These patients with pPCL were younger and had a more aggressive clinical outcome than in multiple myeloma.

Byun JM, Kim D, Shin DY, et al.
Combination of Genetic Aberration With International Staging System Classification for Stratification of Asian Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation.
In Vivo. 2019 Mar-Apr; 33(2):611-619 [PubMed] Free Access to Full Article Related Publications
BACKGROUND/AIM: The aim of the study was to contribute to the development of adaptive risk stratification methods specific to Asian multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT).
PATIENTS AND METHODS: We conducted this study to evaluate the prognostic impact of genetic abnormalities detected by fluorescent in situ hybridization (FISH) on survival outcomes in combination with the International Staging System (ISS) classification in 161 MM patients. This was a single-center retrospective longitudinal cohort study of newly diagnosed MM patients undergoing ASCT within 12 months from initial diagnosis. A single-center retrospective cohort study of newly diagnosed MM.
RESULTS: Patients were divided into 3 groups according to risk stratification: 1) low-risk, patients without del(17p13) nor t(14;16) or t(4;14) and ISS I/II; 2) high-risk, patients with t(4;14), regardless of ISS stage; 3) intermediate-risk, all remaining patients. The median PFS for the low-risk group was 18 months versus 13 months for the intermediate group (p=0.047, HR=1.527, 95%CI=1.006-2.316) versus 10 months for the high-risk group (p<0.001, HR=2.656, 95%CI=1.572-4.490).
CONCLUSION: An ISS/FISH-based prognostication strategy was developed that can predict PFS for Asian MM patients undergoing ASCT.

Niebudek K, Balcerczak E, Mirowski M, Żebrowska M
Association of ABCB1 T-129C polymorphism and multiple myeloma risk in Polish population.
Pol J Pathol. 2018; 69(4):405-409 [PubMed] Related Publications
The possible interaction between gene polymorphism and cancer risk development is a very interesting issue. The genetic variants of the ATP-binding cassette superfamily B member 1 (ABCB1) are known to be involved in developing cancer risk and individual differences in chemotherapeutic response. Polymorphisms may affect the reduction of the activity and/or expression of important protective cellular proteins. The increased exposure to toxic compounds, including carcinogens is associated with an increased risk of developing cancers. The present study was aimed to evaluate the possible effect of ABCB1 T-129C single nucleotide polymorphism in risk of cancer development in Polish patients diagnosed with multiple myeloma. 91 multiple myeloma patients and 94 healthy controls were enrolled in this case-control study. The ABCB1 T-129C genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). The distribution of particular genotypes between multiple myeloma patients and controls group was not significantly different for T-129C SNP (p = 0.4297). The studied polymorphism does not seem to affect the increased risk of multiple myeloma development.

Corrado C, Costa V, Giavaresi G, et al.
Long Non Coding RNA H19: A New Player in Hypoxia-Induced Multiple Myeloma Cell Dissemination.
Int J Mol Sci. 2019; 20(4) [PubMed] Free Access to Full Article Related Publications
The long non-coding RNA H19 (lncH19) is broadly transcribed in the first stage of development and silenced in most cells of an adult organism; it appears again in several tumors where, through different molecular mediators, promotes cell proliferation, motility and metastases. LncH19 has been associated with hypoxia-inducible factor 1-alpha (HIF-1α) activation and, in some tumors, it has proved to be necessary and required to sustain hypoxic responses. Here we propose to investigate a putative role for the lncH19 in hypoxia induced multiple myeloma (MM) progression. Transcriptional analysis of MM cell lines (RPMI and MM1.S) exposed to normoxia or hypoxia (1% O₂) was done in order to evaluate lncH19 levels under hypoxic stimulation. Then, to investigate the role of lncH19 in hypoxia mediated MM progression, transcriptional, protein and functional assays have been performed on hypoxia stimulated MM cell lines, silenced or not for lncH19. Our data demonstrated that hypoxic stimulation in MM cell lines induced the overexpression of lncH19, which, in turn, is required for the expression of the hypoxia induced genes involved in MM dissemination, such as C-X-C Motif Chemokine Receptor 4 (CXCR4) and Snail. Moreover, adhesion assays demonstrated that lncH19 silencing abrogates the increased adhesion on stromal cells induced by the hypoxic condition. Finally, Western blot analysis indicated that lncH19 silencing impaired HIF1α nuclear translocation. The LncH19, required for the induction of hypoxic responses in MM cells, could represent a new therapeutic target for MM.

Zang YZ, Chen XL, Bai YL, et al.
[Expression and Clinical Significance of C/EBPα Gene in Elderly Multiple Myeloma].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2019; 27(1):123-128 [PubMed] Related Publications
OBJECTIVE: To investigate the expression of C/EBPα gene in elderly patients with multiple myeloma (MM) and its prognostic significance.
METHODS: Sixty-nine olderly patients with multiple myeloma (MM) treated in our hospital from February 2015 to October 2017 were selected and enrolled in the MM group, 38 healthy persons received physical examination were selected and enrolled in the control group. The bone marrow of 2 groups was collected and the mononuclear cells were isolated.The mRNA expression level of C/EBPα gene in mononuclear cells was determined by RT-PCR, the Western blot was used to detect the protin expression level of PBMNC C/EBPα, and the protein level of C/EBPα in bone marrow was detected by immunohistochemistry. The correlations of C/EBPα gene expression with the clinical characteristics and survival time in MM patients were analyzed.
RESULTS: The expression level of mRNA and protein of C/EBPα in MM patients was significantly lower than that in the control group (P<0.05). The expression level of C/EBPα gene significantly correlated with the ISS stage, CRP, Calcium, β2-MG, LDH and the percentage of myeloma cells in MM patients (P<0.05). The expression of C/EBPα gene was not correlate with sex, age, immunoglobulin typing, Hb in MM patients (P>0.05).Immunohistochemical staining showed that the bone marrow samples of the control group were stained more deeply, and the staining intensity in bone marrow samples of MM patients with CR, PR and relapse was successively descended. The protein level of C/EBPα in CR patients with MM was significantly higher than that in PR and relapsed patients by Western blot (P<0.05). Kaplan-Meier survival analysis showed that OS and DFS in the patients with high expression of C/EBPα gene were higher than those in low expression group (P<0.05). Multivariate Cox regression analysis showed that CRP,ratio of myeloma cells and C/EBPα gene were independent factors affecting OS and PFS (P<0.05).
CONCLUSION: The expression level of C/EBPα gene in MM patients is low that may stimulate the genesis of MM, and the expression of C/EBPα gene closely relates with the development of MM disease.

Morgan JJ, McAvera RM, Crawford LJ
TRAF6 Silencing Attenuates Multiple Myeloma Cell Adhesion to Bone Marrow Stromal Cells.
Int J Mol Sci. 2019; 20(3) [PubMed] Free Access to Full Article Related Publications
The bone marrow (BM) microenvironment plays an important role in supporting proliferation, survival and drug resistance of Multiple Myeloma (MM) cells. MM cells adhere to bone marrow stromal cells leading to the activation of tumour-promoting signaling pathways. Activation of the NFκB pathway, in particular, is central to the pathogenesis of MM. Tumour necrosis factor receptor-associated factor 6 (TRAF6) is a key mediator of NFκB activation and has previously been highlighted as a potential therapeutic target in MM. Here, we demonstrate that adherence of MM cell lines to stromal cells results in a reciprocal increase in TRAF6 expression. Knockdown of TRAF6 expression attenuates the ability of MM cells to bind to stromal cells and this is associated with a decrease in NFκB-induced expression of the adhesion molecules ICAM1 and VCAM1. Finally, we show that knockdown of TRAF6 sensitizes MM cells to treatment with bortezomib when co-cultured with stromal cells. Inhibiting TRAF6 represents a promising strategy to target MM cells in the BM microenvironment.

Li H, Li F, Zhou X, et al.
Achieving minimal residual disease-negative by multiparameter flow cytometry may ameliorate a poor prognosis in MM patients with high-risk cytogenetics: a retrospective single-center analysis.
Ann Hematol. 2019; 98(5):1185-1195 [PubMed] Related Publications
The aim of our study was to evaluate the prognostic impact of minimal residual disease (MRD) and high-risk cytogenetics (HRCs) on outcomes in multiple myeloma (MM) patients. We applied multiparameter flow cytometry (MFC) to detect MRD in 123 consecutive patients diagnosed with MM for the first time who achieved very good partial remission (VGPR) or better after bortezomib or thalidomide-based induction therapy. Moreover, we examined the cytogenetic features of MM patients using magnetic-activated cell sorting and interphase fluorescence in situ hybridization (MACS-iFISH) at diagnosis. In all 123 MM patients, progression-free survival (PFS) and overall survival (OS) were better in the MRD- group (n = 31) than in the MRD+ group (n = 92) (median PFS: not reached (NR) vs. 26 months (m), P = 0.0002; 4-year OS, 91.7% vs. 66.3%, P = 0.008). PFS and OS were significantly shorter for each increase of one log per MRD level (P < 0.0001 and P = 0.001). The median PFS of the four groups according to the ratio of aberrant plasma cells (less than 0.01%, 0.01-0.1%, 0.1-1%, and more than 1%) were NR, 37 m, 26 m, and 15 m, respectively, and the 4-year OS rates were 91.7%, 69.3%, 76.1%, and 54.0%, respectively. In addition, our results show that PFS and OS were better for the standard-risk cytogenetic (SRC) patients than the HRC patients (median PFS: NR vs. 26 m, P = 0.004; 3-year OS: 95.8% vs. 76.0%, P = 0.006). The independent predictors of PFS were HRC and MRD+, which had hazard ratios of 1.901 (95% CI 1.094-3.303) and 3.486 (95% CI 1.449-8.386), respectively; while those for OS were an LDH level ≥ 250 U/L, HRC, and MRD+, which had hazard ratios of 2.789 (95% CI 1.080-7.199), 2.697 (95% CI 1.053-6.907), and 7.714 (95% CI 1.040-57.227), respectively. Furthermore, for SRC patients or HRC patients, PFS and OS were all longer in MRD- than in MRD+ patients. Strikingly, there was no significant difference in PFS or OS between the MRD-HRC and MRD+SRC groups (median PFS 45 vs. 34 m, P = 0.300; 4-year OS 100% vs. 83.6%, P = 0.196). PFS was superior in MRD-SRC than in MRD-HRC (NR vs. 45 m, P = 0.035); however, there was no significant difference in the 4-year OS between MRD-SRC and MRD-HRC (87.5% vs 100%, P = 0.480). MRD+ and HRCs were both independent prognostic factors in MM patients. Moreover, achieving MRD- may ameliorate a poor prognosis in MM patients with HRCs.

Harding T, Baughn L, Kumar S, Van Ness B
The future of myeloma precision medicine: integrating the compendium of known drug resistance mechanisms with emerging tumor profiling technologies.
Leukemia. 2019; 33(4):863-883 [PubMed] Related Publications
Multiple myeloma (MM) is a hematologic malignancy that is considered mostly incurable in large part due to the inability of standard of care therapies to overcome refractory disease and inevitable drug-resistant relapse. The post-genomic era has been a productive period of discovery where modern sequencing methods have been applied to large MM patient cohorts to modernize our current perception of myeloma pathobiology and establish an appreciation for the vast heterogeneity that exists between and within MM patients. Numerous pre-clinical studies conducted in the last two decades have unveiled a compendium of mechanisms by which malignant plasma cells can escape standard therapies, many of which have potentially quantifiable biomarkers. Exhaustive pre-clinical efforts have evaluated countless putative anti-MM therapeutic agents and many of these have begun to enter clinical trial evaluation. While the palette of available anti-MM therapies is continuing to expand it is also clear that malignant plasma cells still have mechanistic avenues by which they can evade even the most promising new therapies. It is therefore becoming increasingly clear that there is an outstanding need to develop and employ precision medicine strategies in MM management that harness emerging tumor profiling technologies to identify biomarkers that predict efficacy or resistance within an individual's sub-clonally heterogeneous tumor. In this review we present an updated overview of broad classes of therapeutic resistance mechanisms and describe selected examples of putative biomarkers. We also outline several emerging tumor profiling technologies that have the potential to accurately quantify biomarkers for therapeutic sensitivity and resistance at genomic, transcriptomic and proteomic levels. Finally, we comment on the future of implementation for precision medicine strategies in MM and the clear need for a paradigm shift in clinical trial design and disease management.

Govindasamy P, Pandurangan P, Tarigopula A, et al.
Cytogenetic Abnormalities in Multiple Myeloma Patients at a Tertiary Healthcare Center in India
Asian Pac J Cancer Prev. 2019; 20(1):235-241 [PubMed] Free Access to Full Article Related Publications
Objective: Multiple myeloma (MM) is a clinically and genetically heterogeneous plasma cell neoplasm. The prognosis of MM patients is dependent on several factors including the patient’s age, the stage of disease and genetic alterations. This study aimed to determine the frequency of common chromosomal abnormalities and their significance in MM patients referred to a tertiary healthcare center in India. Methods: Fluorescence in situ hybridization on interphase nuclei from bone marrow cells using seven MM-specific probes for recurrent aberrations was performed in a total of 215 newly diagnosed patients. Results: Chromosomal abnormalities were detected in 161 (74.9%) MM patients in this study. The most frequent aberration was trisomy(ies) involving only gain of chromosomes in 48 (22.3%) cases. A translocation involving the IGH gene alone or accompanied by trisomy(ies) or by monosomy 13/13q deletion or by both was registered in 80 (37.2%) patients. Atypical patterns such as a deletion of the IGH variable segment (IGHv) on the derivative chromosome 14 or on the native (normal) chromosome 14, biallelic deletion of IGHv, deletion of the IGH constant segment on the rearranged chromosome14 and extra fusions were noticed in 21 (9.8%) patients with an IGH rearrangement. Monosomy 13/deletion 13q was identified singly or as part of a complex karyotype in 74 patients (34.4%). Clonal heterogeneity and additional abnormalities including TP53 deletion and monosomies of chromosomes 4, 9, 14 and 16 were recorded in 18.6% and 16.3% of patients respectively. Patients with abnormalities exhibited plasmacytosis, reduced hemoglobin value and high level of ß2-microglobulin. Conclusions: A lower median age and a low frequency of IGH translocations particularly t(11;14) and chromosome 13 abnormalities suggest ethnic diversity. Further investigations on genetic alterations including IGH deletions will contribute to improved insights into the biology of myeloma disease, risk stratification and patient management.

Qu S, Liao L, Xie Y, et al.
[Intracranial involvement in newly diagnosed multiple myeloma with TP53 deletion: Two case reports].
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2018; 43(11):1272-1275 [PubMed] Related Publications
We report two rare cases of multiple myeloma (MM) with dural intracranial disease and TP53 deletion. The two patients presented with skull lytic lesion and dural involvement of myeloma. The association between intracranial involvement in MM and TP53 deletion has not been determined. The two patients received bortezomib-based intensive induction and got good response, just as that reported in literature. MM presenting with dural intracranial disease and TP53 deletion at diagnosis is associated with poor outcome. Multi-drug regime containing bortezomib followed by autologous or allogeneic stem cell transportation would improve the prognosis.

Chen L, Fan F, Deng J, et al.
Clinical characteristics and prognosis of immunoglobulin D myeloma in the novel agent era.
Ann Hematol. 2019; 98(4):963-970 [PubMed] Related Publications
Immunoglobulin D (IgD) myeloma is a rare subtype that used to lead to a poor outcome. To investigate the current clinical features, cytogenetic changes and survival of patients with IgD myeloma under novel treatments, we analysed 47 patients with IgD myeloma, 31 men and 16 women, with a median age of 54.5 years. We found that IgD myeloma was associated with higher frequencies of anaemia, renal failure, and hypercalcemia and higher levels of serum LDH compared with non-IgD myeloma. More than 90% of patients with IgD myeloma had at least one cytogenetic abnormality demonstrated by fluorescence in situ hybridisation (FISH). IGH translocations were the most common abnormalities, which were mainly caused by t(11;14). Moreover, 36.2% of patients were at the Revised International Staging System (RISS) stage III when diagnosed. Those patients had significantly shorter PFS and OS compared with patients at RISS stages I and II. In conclusion, IgD myeloma has specific clinical characteristics. The RISS grade was shown to be a simple and effective method to predict the prognosis of patients with IgD myeloma.

Kobayashi H, Abe Y, Miura D, et al.
Prevalence and clinical implications of t(11;14) in patients with amyloid light-chain amyloidosis with or without concurrent multiple myeloma.
Jpn J Clin Oncol. 2019; 49(2):195-198 [PubMed] Related Publications
According to fluorescent in situ hybridization, t(11;14) is the most common cytogenetic abnormality in amyloid light-chain (AL) amyloidosis, but its prevalence in patients with AL amyloidosis and concurrent multiple myeloma (MM) remains unknown. We aimed to examine the prevalence of t(11;14) and the differences in clinical characteristics of patients with t(11;14) who had AL amyloidosis with or without concurrent MM. We retrospectively analyzed 40 patients with AL amyloidosis between January 2008 and January 2018 at our institution. The prevalence of t(11;14) was significantly higher in patients with AL amyloidosis alone compared with those with concurrent MM (56.5% vs. 17.6%; P = 0.022). This study suggests that AL amyloidosis patients with concurrent MM have a lower prevalence of t(11;14) than those without MM and that the presence of t(11;14) may be associated with poor prognosis, irrespective of the presence or absence of MM.

Jang JS, Li Y, Mitra AK, et al.
Molecular signatures of multiple myeloma progression through single cell RNA-Seq.
Blood Cancer J. 2019; 9(1):2 [PubMed] Free Access to Full Article Related Publications
We used single cell RNA-Seq to examine molecular heterogeneity in multiple myeloma (MM) in 597 CD138 positive cells from bone marrow aspirates of 15 patients at different stages of disease progression. 790 genes were selected by coefficient of variation (CV) method and organized cells into four groups (L1-L4) using unsupervised clustering. Plasma cells from each patient clustered into at least two groups based on gene expression signature. The L1 group contained cells from all MGUS patients having the lowest expression of genes involved in the oxidative phosphorylation, Myc targets, and mTORC1 signaling pathways (p < 1.2 × 10

Went M, Sud A, Speedy H, et al.
Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology.
Blood Cancer J. 2018; 9(1):1 [PubMed] Free Access to Full Article Related Publications
The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (R

Li Y, Lin Y
Tumor Necrosis Factor Alpha-308G/A Polymorphism and the Risk of Multiple Myeloma: A Meta-Analysis of Pooled Data from Twelve Case-Control Studies
Turk J Haematol. 2019; 36(2):72-80 [PubMed] Free Access to Full Article Related Publications
Objective: Tumor necrosis factor alpha (TNF-α) is an important cytokine involved in inflammation, immune response, and other biological processes. The association between polymorphism -308G/A in its promoter and the risk of multiple myeloma (MM) is not clear. Thus, we conducted a meta-analysis to clarify this question.
Materials and Methods: Twelve eligible studies, which included 2204 MM cases and 3478 controls, were enrolled in our meta-analysis by searching the PubMed, China National Knowledge Infrastructure, Scopus, Web of Science, and Google Scholar databases up to December 2018. The effect of polymorphism -308G/A on MM risk was evaluated by calculating the pooled odds ratio (OR) and the 95% confidence interval (CI). Furthermore, the Q-test and I2 statistical analyses were used to estimate the degree of heterogeneity. Sensitivity analysis was conducted to test the robustness of the meta-analysis results. Publication bias was assessed by Egger’s test and visual inspection of a funnel plot.
Results: In the dominant model, -308G/A polymorphism was associated with reduced MM risk (OR=0.80, 95% CI: 0.65-0.97), and it also demonstrated a significant protective effect with a pooled OR of 0.82 (95% CI: 0.68-0.99) in the Caucasian subgroup. Because of the limited number of individual studies with AA genotype carriers, only eight studies were included in the recessive model, and no significant difference was observed. Moreover, the meta-analysis of the allele frequency demonstrated that the A allele has a protective effect against MM risk with a pooled OR of 0.83 (95% CI: 0.69-0.99). Sensitivity analysis suggested that the synthesized effect size was not influenced by any individual study. Moreover, the Egger’s test statistical analysis suggested that publication bias was not obvious in the present analysis.
Conclusion: Overall, the -308G/A polymorphism was associated with reduced MM risk in the dominant model and allele frequency. Further investigation is needed to gain better insight.

Kaur G, Gupta R, Mathur N, et al.
Clinical impact of chromothriptic complex chromosomal rearrangements in newly diagnosed multiple myeloma.
Leuk Res. 2019; 76:58-64 [PubMed] Related Publications
Complex Chromosomal Rearrangements (CCRs) are increasingly being reported as genetic risk factors of clinical significance in cancer owing to their identification using high resolution whole genome profiling technologies. This study employed high resolution CGH + SNP microarrays for whole genome copy number variations (CNV) profiling and identified CCRs in 11/107(10%) newly diagnosed Multiple Myeloma (MM) patients. Six patients exhibited Chromothripsis (CTH) among seven chromosomes that were confirmed with automated CTLPscanner web tool and; five cases displayed chromoplexy (CPL) which involved multiple chromosomes. Presence of chromothripsis in chromosome 17 in three out of six patients indicate a link between TP53 aberrations and incidence of CTH. Multivariable Cox regression model demonstrated a significant association of CTH with poor PFS (HR = 3.09, p = 0.010) and OS (HR = 3.31, p = 0.024) which suggests that CTH is an additional independent prognostic marker in multiple myeloma. Addition of CTH in risk stratification models in clinical setting in multiple myeloma may help in upfront identification of high risk patients for suitable customized therapy.

Yao Q, Morgan GJ, Chim CS
Distinct promoter methylation profile reveals spatial epigenetic heterogeneity in 2 myeloma patients with multifocal extramedullary relapses.
Clin Epigenetics. 2018; 10(1):158 [PubMed] Free Access to Full Article Related Publications
Spatial and subclonal genetic heterogeneity in multiple myeloma (MM) have been demonstrated by sequencing of plasma cells from multi-focal regions, but studies of spatial epigenetic heterogeneity are scanty. Herein, promoter methylation status of genes implicated in disease progression (CDKN2A and SHP1) and marrow escape (CDH1, CD56, and CXCR4) was studied in two patients with multi-focal extramedullary relapses. Patient 1 developed simultaneous chest wall and duodenal plasmacytoma at relapse. While SHP1 and CDKN2A were hypermethylated in both plasmacytomas, CDH1 hypermethylation was detected only in the chest wall. In patient 2, SHP1 methylation was found in the extradural plasmacytoma but not bone marrow (BM) at diagnosis, and the circulating PCs but not the BM at relapse. As the clonality, based on sequence of the complementarity-determining region 3 (CDR3) of the immunoglobulin gene, was conserved in plasma cells at diagnosis and relapse, differential methylation of CDH1 in patient 1 and SHP1 in patient 2 was an illustration of spatial epigenetic heterogeneity. Furthermore, subclonal epigenetic heterogeneity was identified by the presence of subclonal SHP1 promoter methylation within the chest wall plasmacytoma of patient 1. In summary, our data showed distinct promoter methylation profile of plasma cells from multiple regions. This is the first report of spatial epigenetic heterogeneity in MM.

Cultrara CN, Kozuch SD, Ramasundaram P, et al.
GRP78 modulates cell adhesion markers in prostate Cancer and multiple myeloma cell lines.
BMC Cancer. 2018; 18(1):1263 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Glucose regulated protein 78 (GRP78) is a resident chaperone of the endoplasmic reticulum and a master regulator of the unfolded protein response under physiological and pathological cell stress conditions. GRP78 is overexpressed in many cancers, regulating a variety of signaling pathways associated with tumor initiation, proliferation, adhesion and invasion which contributes to metastatic spread. GRP78 can also regulate cell survival and apoptotic pathways to alter responsiveness to anticancer drugs. Tumors that reside in or metastasize to the bone and bone marrow (BM) space can develop pro-survival signals through their direct adhesive interactions with stromal elements of this niche thereby resisting the cytotoxic effects of drug treatment. In this study, we report a direct correlation between GRP78 and the adhesion molecule N-cadherin (N-cad), known to play a critical role in the adhesive interactions of multiple myeloma and metastatic prostate cancer with the bone microenvironment.
METHODS: N-cad expression levels (transcription and protein) were evaluated upon siRNA mediated silencing of GRP78 in the MM.1S multiple myeloma and the PC3 metastatic prostate cancer cell lines. Furthermore, we evaluated the effects of GRP78 knockdown (KD) on epithelial-mesenchymal (EMT) transition markers, morphological changes and adhesion of PC3 cells.
RESULTS: GRP78 KD led to concomitant downregulation of N-cad in both tumors types. In PC3 cells, GRP78 KD significantly decreased E-cadherin (E-cad) expression likely associated with the induction in TGF-β1 expression. Furthermore, GRP78 KD also triggered drastic changes in PC3 cells morphology and decreased their adhesion to osteoblasts (OSB) dependent, in part, to the reduced N-cad expression.
CONCLUSION: This work implicates GRP78 as a modulator of cell adhesion markers in MM and PCa. Our results may have clinical implications underscoring GRP78 as a potential therapeutic target to reduce the adhesive nature of metastatic tumors to the bone niche.

García R, Chen W, Koduru P
Clinical impact of MYC abnormalities in plasma cell myeloma.
Cancer Genet. 2018; 228-229:115-126 [PubMed] Related Publications
Clinically and genomically, plasma cell myeloma (PCM) is a complex disease affecting the elderly population and has often had a poor prognosis. Karyotypic analysis of tumor cells is somewhat limited due to a low proliferative index coupled with a low frequency of tumor cells in clinical samples. Nevertheless, complex karyotypes with a multitude of numerical, balanced and unbalanced structural aberrations have been reported in these tumors. In this study we evaluated the karyotypes obtained in a single institution to identify recurring cytogenetic abnormalities. We constructed evolutionary pathways to differentiate abnormalities present at the beginning of evolution from those that developed later in evolution. We then estimated genetic progression scores and the clinical impact of the cytogenetic abnormalities on survival. In addition, we also evaluated the clinical significance of MYC related abnormalities (translocations and numerical changes) in disease evolution and on survival. Our results indicate that PCM with MYC related abnormalities in general have advanced tumors and adverse outcomes even with low proliferation. Trisomy 8 also contributes to unfavorable outcomes in PCM, this has not been reported previously.

Tian F, Zhan Y, Zhu W, et al.
MicroRNA-497 inhibits multiple myeloma growth and increases susceptibility to bortezomib by targeting Bcl-2.
Int J Mol Med. 2019; 43(2):1058-1066 [PubMed] Related Publications
Multiple myeloma (MM) is a common severe hematopoietic malignancy occuring in aged population. MicroRNA (miR)‑497 was previously reported to contribute to the apoptosis of other cell types, presumably through targeting B‑cell lymphoma 2 (Bcl‑2). In the present study, miRNA and protein expression levels were detected by reverse transcription‑quantitative polymerase chain reaction and western blot analyses, respectively. The cell proliferation and viability was measured using 3‑(4,5‑dimethylthiazol‑2‑yl)‑2, 5‑diphenyltetrazolium bromide and plate clonality assays, and the cell growth cycle was measured with a flow cytometer. Terminal deoxynucleotidyl transferase (TdT)‑mediated dUTP nick‑end‑labeling, Annexin V and caspase‑3 activity assays were performed to examine the cell apoptotic rates. The results showed that miR‑497 was markedly decreased, whereas Bcl‑2 was enhanced in MM tissues and cell lines. miR‑497 targeted Bcl‑2 and affected its downstream apoptosis‑related genes. The overexpression of miR‑497 promoted MM cell apoptosis through cell cycle arrest, and decreased colony genesis ability and viability. In addition, miR‑497 increased the sensitivity of MM cells to bortezomib. Taken together, miR‑497 suppressed MM cell proliferation and promoted apoptosis by directly targeting Bcl‑2 and altering the expression of downstream apoptosis‑related proteins. The combination of miR‑497 and bortezomib may enhance drug sensitivity, serving as a potentially available therapeutic method for MM.

Wang CB, Wu J, Yang K, et al.
[Retrospective Analysis of Genetics Abnormalities in Patients with Multiple Myeloma].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2018; 26(6):1681-1687 [PubMed] Related Publications
OBJECTIVE: To explore the characteristics of cytogenetics and molecular genetics in patients with multiple myeloma(MM).
METHODS: Fluorescence in situ hybridization(FISH) was used for molecular genetics analysis in 86 cases of newly diagnosed MM, at the same time the chromosome karyotype analysis was performed in 20 cases. Specimen were bone marrow cells.
RESULTS: FISH detection showed that 68 cases of MM (79.07%) had at least one type of the molecular genetic abnormalities. The positive rates of IgH rearrangement, 1q21 amplification, D13S319 deletion, RB1 deletion and.P53 deletion were 62.79%, 26.74%, 24.42% ,13.95% and 1.16%, respectively. The positive rate of IgH was significantly higher than that of any other probes(P<0.01). The positive rate of IgH was 79.41% in 68 cases. Out of which the positive rate of IgH single and combined with 1, 2, 3, 4 probes was 59.26%, 24.07%, 11.11%, 5.56% and 0 respectively. The positive rate of IgH only was very signficantly higher than that of combined with any other probes(P<0.01).The positive rate of 1q21 was 33.82% in 68 cases, Out of which the positive rates of 1q21 or combined with 1,2,3,4 probes was 21.74%, 43.48%, 21.74%,13.04% and 0 respectively, the 1q21 probe showed positive as combined with other probes(P<0.01), especially with IgH(P<0.05). The positive rates of D13S319 were 30.88% in 68 cases of patients, out of which the positive rates of D13S319 single or combined with 1, 2, 3, 4 probes was 14.29%, 28.57%, 42.86%, 14.29% and 0 respectively, the D13S319 combined with other probes appeared more significant positive(P<0.01), especially with 1 or 2 probes (P< 0.01). The positive rate of RB1 was 17.65% in 68 cases, the positive rate of RB1 singl or combined with 1, 2, 3, 4 probes were 0, 25%, 50%, 25% and 0, the RB1 appeared positive always combined with other probes, especially with D13S319 probe (P<0.01). The positive rate of P53 was 1.47%, as combined with RB1 and D13S319 probes. The chromosomal karyotyping showed that 3 cases carried abnormal chromosomal and 17 cases carried normal chromosome, Out of which 17 cases showed positive by FISH. There was a significant difference of sensitivity between FISH combined with chromosome karvotyping and single chromosome karvotype (P< 0.01).
CONCLUSION: The genetic abnormalies display obvious heterogenicity in MM. The sensitivity of FISH is higher than that of chromosomal karvotyping. If FISH and chromosome karvotyping are combined, the positive rate of abnormality can be raised.

Xie Z, Chooi JY, Toh SHM, et al.
MMSET I acts as an oncoprotein and regulates GLO1 expression in t(4;14) multiple myeloma cells.
Leukemia. 2019; 33(3):739-748 [PubMed] Related Publications
Multiple myeloma (MM) is characterized by recurrent chromosomal translocations. T(4;14) MM overexpresses multiple myeloma SET domain-containing protein (MMSET). MMSET has three major isoforms: the full-length form MMSET II and the short isoforms REIIBP and MMSET I. Here we show that the short isoform MMSET I is an oncoprotein that promoted cell survival and tumorigenesis in vitro and in vivo. Gene expression array analysis indicated that MMSET I increased glyoxalase I (GLO1) expression. Chromatin immunoprecipitation (ChIP) coupled with qPCR indicated that MMSET I bound upstream of the GLO1 transcription start site. Ectopic overexpression of MMSET I or its mutants showed MMSET I depended on its C terminus to regulate GLO1 expression. GLO1 knockdown (KD) induced apoptosis and reduced colony formation. MMSET I or GLO1 KD reduced the levels of anti-apoptosis factors such as MCL1 and BCL2. Ectopic overexpression of GLO1 resulted in the significant rescue of KMS11 cells from MMSET I KD-induced apoptosis and glycolysis inhibition. This suggested that GLO1 may be of functional importance target downstream of MMSET I. Cumulatively, our study suggests that MMSET I is an oncoprotein and potential therapeutic target for t(4;14) MM.

Zhou L, Jiang H, Du J, et al.
USP15 inhibits multiple myeloma cell apoptosis through activating a feedback loop with the transcription factor NF-κBp65.
Exp Mol Med. 2018; 50(11):151 [PubMed] Free Access to Full Article Related Publications
USP15 has been shown to stabilize transcription factors, to be amplified in many cancers and to mediate cancer cell survival. However, the underlying mechanism by which USP15 regulates multiple myeloma (MM) cell proliferation and apoptosis has not been established. Here, our results showed that USP15 mRNA expression was upregulated in MM patients. USP15 silencing induced MM cell proliferation inhibition, apoptosis, and the expression of nuclear and cytoplasmic NF-κBp65, while USP15 overexpression exhibited an inverse effect. Moreover, in vivo experiments indicated that USP15 silencing inhibited MM tumor growth and NF-κBp65 expression. PDTC treatment significantly inhibited USP15 overexpression-induced cell proliferation, apoptosis inhibition, and NF-κBp65 expression. USP15 overexpression promoted NF-κBp65 expression through inhibition of its ubiquitination, whereas NF-κBp65 promoted USP15 expression as a positive regulator. Taken together, the USP15-NF-κBp65 loop is involved in MM tumorigenesis and may be a potential therapeutic target for MM.

Shah V, Johnson DC, Sherborne AL, et al.
Blood. 2018; 132(23):2465-2469 [PubMed] Free Access to Full Article Related Publications
Multiple myeloma (MM) is a genetically heterogeneous cancer of bone marrow plasma cells with variable outcome. To assess the prognostic relevance of clonal heterogeneity of

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 (6p25.3)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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