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  • 1
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    Online Resource
    The DNA methylation landscape of multiple myeloma shows extensive inter- and intrapatient heterogeneity that fuels transcriptomic variability
    Springer Science and Business Media LLC ; 2021
    In:  Genome Medicine Vol. 13, No. 1 ( 2021-12)
    Details
    In: Genome Medicine, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2021-12)
    Abstract: Cancer evolution depends on epigenetic and genetic diversity. Historically, in multiple myeloma (MM), subclonal diversity and tumor evolution have been investigated mostly from a genetic perspective. Methods Here, we performed an analysis of 42 MM samples from 21 patients by using enhanced reduced representation bisulfite sequencing (eRRBS). We combined several metrics of epigenetic heterogeneity to analyze DNA methylation heterogeneity in MM patients. Results We show that MM is characterized by the continuous accumulation of stochastic methylation at the promoters of development-related genes. High combinatorial entropy change is associated with poor outcomes in our pilot study and depends predominantly on partially methylated domains (PMDs). These PMDs, which represent the major source of inter- and intrapatient DNA methylation heterogeneity in MM, are linked to other key epigenetic aberrations, such as CpG island (CGI)/transcription start site (TSS) hypermethylation and H3K27me3 redistribution as well as 3D organization alterations. In addition, transcriptome analysis revealed that intratumor methylation heterogeneity was associated with low-level expression and high variability. Conclusions We propose that disrupted DNA methylation in MM is responsible for high epigenetic and transcriptomic instability allowing tumor cells to adapt to environmental changes by tapping into a pool of evolutionary trajectories.
    Type of Medium: Online Resource
    ISSN: 1756-994X
    URL: Article
    DOI: 10.1186/s13073-021-00938-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2484394-5
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  • 2
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    Abstract 3035: HDAC8 is recruited to DNA double strand breaks sites and affects the homologous recombination efficiency in multiple myeloma
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3035-3035
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3035-3035
    Abstract: Epigenomic changes have emerged as an important player of cellular regulation and understanding of pathogenesis of Multiple Myeloma (MM) as well as of other cancers. In recent years, both clinical and preclinical studies have confirmed that MM is vulnerable to epigenetic intervention, with histone deacetylases (HDACs) emerging as the most promising epigenetic targets. Although Pan-HDAC inhibitors are effective as therapeutic agents, there is increasing emphasis on understanding the biological and molecular roles of individual HDACs. Here we evaluated the role of HDAC8, a member of Class I HDAC isoenzymes in MM. First, we evaluated the expression of HDAC8 in 172 newly-diagnosed MM patients from the IFM myeloma dataset and observed HDAC8 overexpression as well as its significant correlation with poor survival outcome (P & lt;0.0015). We further evaluated the expression of HDAC8 in HMCLs (probe ID_223909-s_at, 223345_at) and confirmed the high expression and its cytoplasmic and nuclear localization in all MM cells lines studied. The HDAC8 depletion (lentiviral-shRNA)in HMCLs resulted in significant inhibition of proliferation of MM cells as measured by 3[H]-thymidine assay, and as decrease in colony formation evaluated after 3 weeks post transfection (P & lt;.001). We observed similar cell growth inhibition using PCI-34051, a small molecule HDAC8 inhibitor. Interestingly, the combination of HDAC8 inhibitor with melphalan or bendamustine enhanced the anti-MM effects of the DNA damaging agents (all p & lt;0.01). Immunoblotting analysis using a panel of 15 antibodies for DNA damage response (DDR) pathway confirmed increased levels of DNA damage in OPM2 and MM1S cells lacking HDAC8. Consistent with this observation HDAC8 depletion led to decreased homologous recombination (HR) activity as measured by plasmid-based assay. We performed singe cell electrophoresis (Comet-assay) and observed decreased repair of DSBs after IR in OPM2-HDAC8 depleted cells as well as after pharmacologic inhibition of HDAC8. Importantly, using laser micro-irradiation in myeloma and U2OS cells, we observed HDAC8 recruitment to DSBs sites. The HDAC8 was co-localized and co-immunoprecipitated with Rad51 after IR, and with Scm3, member of cohesion complex suggesting its relation with cytoskeleton. In MM1s cells containing a stably integrated Rad51-luciferase reporter construct, the addition of HDAC8 inhibitor suppressed Rad51, confirming the immunoblotting findings. A mass spectromentry-based analysis identified the HDAC8-interacting complexes with cohesion- (cohesin subunit SA-2, Condensin-2) and DDR-key components (Mre11a, XRCC1, Rad50). In conclusion, our results demonstrate impact of epigenomic change on DNA integrity through connection between HDAC8 and DNA damage response pathway, and provide insights into the effect of HDAC8 on DNA stability and cell growth and survival that may have therapeutic implications in MM. Citation Format: Maria Gkotzamanidou, Masood Shammas, Jesús Martín Sánchez, Mehmet Kemal Samur, Stephane Minvielle, Florence Magrangeas, Herve Avet-Loiseau, Athanasios-Meletios Dimopoulos, Kenneth C. Anderson, Nikhil C. Munshi. HDAC8 is recruited to DNA double strand breaks sites and affects the homologous recombination efficiency in multiple myeloma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3035. doi:10.1158/1538-7445.AM2015-3035
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-3035
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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    detail.hit.zdb_id: 410466-3
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  • 3
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    A Genome-Wide Association Study Identifies a Novel Locus for Bortezomib-Induced Peripheral Neuropathy in European Patients with Multiple Myeloma
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 17 ( 2016-09-01), p. 4350-4355
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 17 ( 2016-09-01), p. 4350-4355
    Abstract: Purpose: Painful peripheral neuropathy is a frequent toxicity associated with bortezomib therapy. This study aimed to identify loci that affect susceptibility to this toxicity. Experimental Design: A genome-wide association study (GWAS) of 370,605 SNPs was performed to identify risk variants for developing severe bortezomib-induced peripheral neuropathy (BiPN) in 469 patients with multiple myeloma who received bortezomib–dexamethasone therapy prior to autologous stem cell in randomized clinical trials of the Intergroupe Francophone du Myelome (IFM) and findings were replicated in 114 patients with multiple myeloma of the HOVON-65/GMMG-HD4 clinical trial. Results: An SNP in the PKNOX1 gene was associated with BiPN in the exploratory cohort [rs2839629; OR, 1.89, 95% confidence interval (CI), 1.45–2.44; P = 7.6 × 10−6] and in the replication cohort (OR, 2.04; 95% CI, = 1.11–3.33; P = 8.3 × 10−3). In addition, rs2839629 is in strong linkage disequilibrium (r2 = 0.87) with rs915854, located in the intergenic region between PKNOX1 and cystathionine-ß-synthetase (CBS). Expression quantitative trait loci mapping showed that both rs2839629 and rs915854 genotypes have an impact on PKNOX1 expression in nerve tissue, whereas rs2839629 affects CBS expression in skin and blood. Conclusions: The use of GWAS in multiple myeloma pharmacogenomics has identified a novel candidate genetic locus mapping to PKNOX1 and in the immediate vicinity of CBS at 21q22.3 associated with the severe bortezomib-induced toxicity. The proximity of these two genes involved in neurologic pain whose tissue-specific expression is modified by the two variants provides new targets for neuroprotective strategies. Clin Cancer Res; 22(17); 4350–5. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-15-3163
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 4
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    Abstract 5719: Long intergenic non-coding RNAs: a new independent risk predictors in multiple myeloma
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5719-5719
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5719-5719
    Abstract: RNA has diverse sets of regulatory functions and a recent analysis of RNA repertoire has identified a large numbers of non-coding transcripts. One of which, long intergenic non-coding RNA (lincRNA) with transcripts longer than 200 nucleotides, are located between the protein coding genes and do not overlap exons of either protein-coding or other non-lincRNA genes. lincRNAs have been considered to provide regulatory functions, however, their precise role in cellular biology remains unclear. Here, we have studied lincRNAs using uniformly treated patients to show their impact on survival outcome in MM. We performed RNA-seq on CD138+ MM cells from 360 newly-diagnosed patients and 18 normal plasma cells (NPM) and analyzed for lincRNA and protein coding genes. MM patient data for clinical characteristics, cytogenetic and FISH as well as clinical survival outcomes were also analyzed and correlated with lincRNA data. Our data showed expression of 951 lincRNAs (median TPM & gt; 1) with 351 lincRNAs differentially expressed between MM and normal plasma cells. Using only the expressed lincRNAs, we applied log rank tests for quartile 1 (Q1) versus Q2 through Q4 and Q4 versus Q1 through Q3 in order to identify under- and overexpressed prognostic genes, respectively. Four under and seven overexpressed genes were selected for final model. We used Más-o-menos for final predictive model, which simply calculates the risk score, by using expression values. The Kaplan-Meier estimates of EFS at 4 years were 53.3% (95% CI, 45.1% to 63.1%) and 32.6% (95% CI, 25.1% to 42.2%), and OS at 4 years were 93.2% (95% CI, 88.9% to 97.6%) and 71.1% (95% CI, 62.9% to 80.3%) in our patients having a low or high risk score. When applied to patient cohort separated by other risk categorization including minimal residual disease status (MRD), cytogenetic risk status (del17p, t(4;14) and t(14;16)) and International Staging System (ISS), lincRNA signature was able to further identify patients with significant differential survival outcomes. In summary, we report that lincRNAs have an independent effect on survival outcome in MM and provides rational for its use in risk stratification as well as to understand biological impact. Citation Format: Mehmet K. Samur, Annamaria Gulla, Mariateresa Fulciniti, Anil Aktas Samur, Raphael Szalat, Masood Shamas, Florence Magrangeas, Stephane Minvielle, Kenneth Anderson, Giovanni Parmigiani, Hervé Avet-Loiseau, Nikhil Munshi. Long intergenic non-coding RNAs: a new independent risk predictors in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5719. doi:10.1158/1538-7445.AM2017-5719
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-5719
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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    detail.hit.zdb_id: 410466-3
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  • 5
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    Online Resource
    Constraints on signaling network logic reveal functional subgraphs on Multiple Myeloma OMIC data
    Springer Science and Business Media LLC ; 2018
    In:  BMC Systems Biology Vol. 12, No. S3 ( 2018-3)
    Details
    In: BMC Systems Biology, Springer Science and Business Media LLC, Vol. 12, No. S3 ( 2018-3)
    Type of Medium: Online Resource
    ISSN: 1752-0509
    URL: Article
    DOI: 10.1186/s12918-018-0551-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2265490-2
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  • 6
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    High-Resolution Whole-Genome Copy Number Profiling Identifies High-Risk and Low-Risk Patients with Mantle Cell Lymphoma, a Result of the Lyma-Genomic Project Conducted on Behalf the Lysa Group
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 1745-1745
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1745-1745
    Abstract: Introduction: Prognosis markers available at diagnosis are needed to discriminate high-risk (HR) from low-risk (LR) mantle cell lymphoma (MCL) patients (Delfau-Larue et al. Blood 2005; Balasubramanian et al. ASH 2014 abstract 78). In the present work, we report a whole-genome copy number analysis performed with a new technical approach. Samples from ninety-six young MCL patients treated in the phase III LyMa trial (Le Gouill et al. ASH 2014) have been investigated. Methods: Samples were selected according to material availability and patient's outcome. The cohort included 9 HR patients with primary refractory disease or relapse within one year post-diagnosis and 87 patients still in response one year after diagnosis, including 64 LR patients who were still in complete remission more than 30 months after diagnosis. Lymph node biopsies collected at diagnosis, formalin-fixed and paraffin-embedded were used to extract DNA, even when highly degraded. Both whole-genome copy number profiling and the most frequent somatic mutations of TP53 were analyzed with 50 ng of genomic DNA using the OncoScan® FFPE Assay, a new robust and validated single nucleotide polymorphism (SNP) array (Foster et al. BMC Med Genomics 2015). This assay uses the Molecular Inversion Probe technology (MIP) optimized for highly degraded FFPE samples. The ~200000 probes allowed for the detection of genome-wide copy number alterations (CNAs) with a higher concentration in cancer-related genes. The frequency and prognosis impact of CNAs were evaluated. Results and discussion: Overall, 68 recurrently altered regions were observed in 98% of patients. Deletions were more frequent than amplifications, at 9 vs 3 by patient respectively. Recurrent CNAs included losses at 1p21 (43%), 11q22 (ATM) (40%), 13q14 (24%), 9q22-31 (CDKN2A/CDKN2B) (25%), 13q33-34 (RB1) (21%), 8p11 (18%), 17p13 (TP53) (17%) and gains at 3q26-27 (35%), 3q21 (27%), 10q11 (13%) 15q11 (13%), 11q13 (CCND1) (12%), 13q31 (mir-17-92) (11%), 7p22 (CARD11) (10%), 10p12 (BMI1) (9%), 8q24 (MYC) (8%) and 12q13 (CDK4) (7%). TP53 mutations were detected in 5 patients including two with 17p13 deletion and showed a trend to be more frequent in the HR group vs LR (22% vs 3%; p=0.07). Deletions of TP53 (44% vs 14%; p=0.04), CDKN2A (67% vs 29%; p=0.054) and 8p11 (89% vs 24%; p=0.0002) were more frequent in the HR. The CDK4 (33% vs 6%; p=0.03) and mir-17-92 (44% vs 9%; p=0.01) loci were more frequently amplified in HR patients. Amplification of the miR-17-92 locus could explain why miR-17-92 overexpression, a PI3K/AKT pathway regulator, was associated with a worse prognosis in MCL (Roisman et al. Genes Chromosomes Cancer 2016). In contrast, amplification of the CARD11 locus was associated with LR (16% vs 0%; p=0.03). Conclusion: This study confirms the poor prognostic impact of TP53 alterations and reveals new CNAs associated with HR MCL such as 8p11 deletion and mir-17-92 locus amplification. Conversely CARD11 amplification appears to be associated with LR and absent from HR patients. These findings provide important clues for future theranostic-driven therapies in MCL. Disclosures Hermine: Alexion: Research Funding; Novartis: Research Funding; Celgene: Research Funding; AB science: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.1745.1745
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 7
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    Expression Profile Signature to Predict Response to Bortezomib and Dexamethasone Combination Therapy in Newly-Diagnosed Myeloma: Moving towards Prospective Prediction
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 2746-2746
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 2746-2746
    Abstract: Current therapy for multiple myeloma (MM) remains empiric. Only 30–40% of patients respond to any one agent. Moreover, with each new therapy attempted, patients often experience numerous complications and toxicities requiring specialized intervention. In last 4 years four new agents have been approved for use in MM making selection of effective agents more difficult as well as economically taxing. With the improved understanding of oncogenomics in MM and with an ultimate goal of selecting therapies based on their best chance of success, we have used expression profile of myeloma cells to identify expression signature associated with response or resistance to therapeutic agents. We evaluated 34 newly-diagnosed patients with MM enrolled on IFM protocol 2005-01 and treated with bortezomib and dexamethasone as an induction regimen. 18 patients had achieved CR/nCR while 16 patients had no response or progressive disease on therapy. MM cells were purified from bone marrow samples collected prior to initiation of therapy and expression profile was obtained using Affymetrix Human Exon 1.0 ST arrays and analyzed using the dChip software. We next used the “Sample Classification” module in the dChip software to explore predicting patient response using expression data. When we Use two-sample comparison or ANOVA methods to compare the response and to obtain a gene list, and then use a Linear Discriminant Analysis (LDA) to use these genes as features to train a classifier and predict samples, a prediction accuracy of 97% (33/34) was obtained. For unbiased prediction, we modified dChip to perform a leave-one-out cross-validation. Specifically, for each round, one of the 34 samples is left out and the remaining 33 samples are used to select genes and train the classifier. Then the classifier is used to predict the response of the left-out sample and compare it to the real response of this sample. With this analysis we observed 80% positive predictive value which compares favorably with the present CR ratio in the cohort from which these 34 samples come from. In addition, we also used the same cross-validation method to classify the 8 nCR (immunofixation (IFE) positive CR) versus the 10 CR (IFE negative CR) samples. Although the best achievable overall accuracy is 83%, the accuracy is much more variable than the CR versus NR classification when we vary the gene selection stringency. We also realize and in fact foresee that the expression profile will not be able to predict all patients and due to various factors some samples will not provide clear signature of resistance or sensitivity. A two-group comparison of the response Yes and No samples identified response-related genes. The genes down-regulated in the response group are significantly enriched by genes in Gene Ontology categories “biopolymer glycosylation”, “integral to Golgi membrane”, “transferase activity and gene on chromosome 11q.13. The genes up-regulated in the response group are significantly enriched by genes in Gene Ontology categories “cytoskeleton” and genes on chromosome 12p11 and 4p14. These genes provide a basis for investigating how gene expression and pathways change could affect response to the combination treatment with the two drugs. In conclusion, our preliminary pharmacogenomic studies have confirmed our ability to perform large-scale micro-array profiling from patient bone marrow samples and we have identified gene expression signature associated with responsiveness (CR) versus resistance (NR) to combination of Velcade and dexamethasone. The task ahead is to now prospectively validate our ability to predict whether the combination of bortezomib and dexamethasone will be effective in a given patient.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.2746.2746
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
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  • 8
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    Bone Marrow Microenvironment Affects The Pathogenesis Of Multiple Myeloma Through Downregulation Of Alternative Splicing Factor Fox2 In Myeloma Cells
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 3085-3085
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 3085-3085
    Abstract: Alternate splicing is an important post translational change that alters specificity of gene function. Misregulation of alternative splicing has been implicated in number of disease processes including cancer. We have analyzed alternate splicing in myeloma using high throughput GeneChip Human Exon 1.0 ST Arrays in 170 uniformly treated patients and identified pattern of splicing as well as their impact on both overall and event free survival in myeloma. We have now further analyzed this data and identified Fox2, a RNA alternative splicing regulator, as one of the most important genes predicting clinical outcome in these patients. We observe that the expression level of Fox2 correlates with the frequency of RNA splicing and disease prognosis in MM patients. We have now further investigated the molecular role of Fox2 in myeloma. Fox2 expression was detected in all 10 MM cell lines tested at both RNA and protein levels. Immunohistochemistry staining showed a predominant nuclear localization of Fox2. We next evaluated impact of IL-6 on Fox2 expression in MM1S and RPMI8226 MM cell lines and observed dose-dependent reduction in Fox2 expression. Importantly, MM cell - bone marrow stromal cells (BMSC) interaction also led to significant inhibition of Fox2 expression in MM1S and RPMI8226 cells. Similar response was also observed using BMSC supernatants. On the other hand, IGF-1 stimulation showed slight upregulation of Fox2 in MM cell lines. We have also evaluated impact of IL-6 on Fox2 and splicing using genomewide RNA-seq and confirmed the results. Fox2 was downregulated 33% in MM1S and 37% in RPMI8226 at gene expression level. To study its role in MM, we knocked down the expression of Fox2 in MM1S and RPMI8226 cell lines by using Fox2-directed siRNA. Compared to control cell lines, Fox2 knockdown in MM cell lines did not affect the cell proliferation and survival, as measured by cell titer glo luminescent cell viability assay and annexin V and PI staining respectively. Since Fox2 has been described to plays a role in the maintenance of cell cytoskeleton, we therefore evaluated whether Fox2 might influence the migration and adhesion in MM cells. Transwell migration assay showed enhanced migration rate of Fox2-knocking down- MM1S and RPMI8226 cells versus controls. We also observed the increased cell adhesion to fibronetin in both cell lines upon Fox2 knockdown. Actin polymerization evaluated by Alexa488-conjugated phalloidin staining and confocal microscope analysis showed Fox2 knocking down cells with increased actin polymerization in both MM1S and RPMI8226 cell lines. Currently, RNA seq data following Fox2 knock down in MM cell lines is being evaluated to define the molecular mechanisms of bone marrow microenvironment-mediated Fox2-regualted alternative splicing events in MM. In summary, our results identify Fox2 as a biologically important splicing factor with essential function and potential clinical implications in multiple myeloma. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.3085.3085
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
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    Role of additional chromosomal changes in the prognostic value of t(4;14) and del(17p) in multiple myeloma: the IFM experience
    American Society of Hematology ; 2015
    In:  Blood Vol. 125, No. 13 ( 2015-03-26), p. 2095-2100
    Details
    In: Blood, American Society of Hematology, Vol. 125, No. 13 ( 2015-03-26), p. 2095-2100
    Abstract: Additional chromosomal changes modulate the outcome of patients with high-risk multiple myeloma.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2014-07-587964
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
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  • 10
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    Functional and Genomic Signatures of Homologous Recombination (HR) Predict for Clinical Outcome in Multiple Myeloma (MM)
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 3626-3626
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 3626-3626
    Abstract: Homologous recombination (HR) is a DNA repair mechanism based on extensive sequence homology betyween DNA molecules. In a normal cellular environment, the branch of HR which is utilized to copy missing or altered information from a sister chromatid in the G2 phase of the cell cycle, is one of the most tightly regulated and error-free DNA repair mechanism. Thus HR, especially the one associated with G2 phase of cell cycle, has a unique role in the maintenance of genomic integrity and stability. However, we have previously observed that, in vitro, elevated or dysregulated HR activity mediates genomic instability and development of drug resistance in multiple myeloma (MM). In this study we have now evaluated clinical significance of elevated HR activity in MM. We optimized an in vitro HR assay using cell lysates and demonstrated that evaluation of HR with this assay is consistent with assay conducted with intact cells (R=0.97; P=0.0005). Using this assay, we evaluated HR activity in 100 patient specimens. We found that HR activity was elevated ³2-fold relative to normal PBMC in 69% and ³4-fold in 20% of MM samples. At 47 months 74% of patients with very high HR (³4-fold) had event where as 45% of patients with lower HR had event (P=0.049) To further define genomic signature of elevated HR activity, we performed RNASeq on these patient samples (N=65) and identified 345 genes whose expression correlated with HR activity in MM. Expression of 147 genes correlated positively with HR activity (R, ≥ 0.3; P ≤ 0.01). Higher expression of 65 of these genes significantly associated with poor event free survival (EFS). Expression of 198 genes correlated negatively with HR activity (R, ≥ -0.3; P ≤ 0.01). TP53, a known negative regulator of HR, was among top five in this list. Lower expression of 26 of these potential negative regulators of HR associated with poor EFS. The genes correlating with HR activity in myeloma include novel genes (previously not shown to have association with HR), genes previously known to regulate HR, as well as the genes recently identified as HR regulators in other cancers. Gene network analyses showed that the novel HR genes identified in our signature belonged to a variety of functional groups including those involved in signal transduction by phosphorylation, chromatin organization, chromosome function, cytoskeleton function, cellular response to stimulus, response to stress, DNA/nucleic acid binding, DNA/nucleic acid metabolic process, nuclear metabolic process, nucleolus function, cell cycle, and proliferation. The network analysis is consistent with the view that the novel genes identified in this signature may have roles in DNA repair and genome maintenance. We also tested HR correlating genes for correlation with genomic instability (by investigating copy number changes) in a unique MM dataset (gse26863) and found that 50% of the genes significantly correlated with genomic instability. Elevated expression of MCM5, one of the genes in myeloma HR signature, significantly correlated with hyperdiploidy in MM (P≤0.004). Some of the novel genes, including negative regulators of HR, are currently being confirmed for their impact on HR and genome stability in loss and gain of function studies. In summary, we have developed a novel clinically applicable assay for HR activity and present evidence of prognostic significance of high HR activity in myeloma and have identified novel targets with potential to overcome/reduce dyregulated HR and genomic instability. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.3626.3626
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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