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Myeloma genomics

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https://www.readbyqxmd.com/read/29130642/dual-inhibition-of-dnmts-and-ezh2-can-overcome-both-intrinsic-and-acquired-resistance-of-myeloma-cells-to-imids-in-a-cereblon-independent-manner
#1
Konstantinos Dimopoulos, Alexandra Søgaard Helbo, Helga Fibiger Munch-Petersen, Lene Sjö, Jesper Christensen, Lasse Sommer Kristensen, Fazila Asmar, Emil Hermansen, Casey O'Connel, Peter Gimsing, Gangning Liang, Kirsten Grønbaek
Thalidomide and its derivatives, lenalidomide and pomalidomide (also known as IMiDs), have significantly changed the treatment landscape of multiple myeloma, and the recent discovery of cereblon (CRBN) as their direct biological target has led to a deeper understanding of their complex mechanism of action. In an effort to comprehend the precise mechanisms behind the development of IMiD resistance and examine whether it is potentially reversible, we established lenalidomide- (-LR) and pomalidomide-resistant (-PR) human myeloma cell lines from two IMiD-sensitive cell lines, OPM2 and NCI-H929, by continuous culture in the presence of lenalidomide or pomalidomide for 4-6 months, until acquirement of stable resistance...
November 11, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29019452/minimal-residual-disease-analysis-in-myeloma-when-why-and-where
#2
Uday Yanamandra, Shaji K Kumar
The primary hurdle in the path to curing multiple myeloma (MM) is defining a validated minimal residual disease (MRD) and its utility in the therapeutic decision making. A better definition of MRD will aid in tailoring MM therapy further to address the clonal heterogeneity and genomic instability and overcome patient's ineffective immune surveillance. MRD analysis can define the logical endpoint for maintenance therapy, in addition also aids in providing a better clinical end point for studies comparing novel agents in myeloma...
October 11, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28966938/rna-processing-a-new-player-of-genomic-instability-in-multiple-myeloma
#3
EDITORIAL
Matteo Marchesini, Elena Fiorini, Simona Colla
No abstract text is available yet for this article.
July 2017: Oncoscience
https://www.readbyqxmd.com/read/28958990/crispr-genome-wide-screening-identifies-dependence-on-the-proteasome-subunit-psmc6-for-bortezomib-sensitivity-in-multiple-myeloma
#4
Chang-Xin Shi, K Martin Kortüm, Yuan Xiao Zhu, Laura A Bruins, Patrick Jedlowski, Patrick G Votruba, Moulun Luo, Robert A Stewart, Jonathan Ahmann, Esteban Braggio, A Keith Stewart
Bortezomib (BTZ) is highly effective in the treatment of Multiple Myeloma (MM), however emergent drug resistance is common. Consequently, we employed CRISPR targeting 19,052 human genes to identify unbiased targets that contribute to BTZ resistance. Specifically, we engineered an RPMI8226 MM cell line to express Cas9 and a lentiviral-vector CRISPR library and cultured derived cells in doses of BTZ lethal to parental cells. Sequencing was performed on surviving cells to identify inactivated genes responsible for drug resistance...
September 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28943951/recurrent-alterations-of-the-ww-domain-containing-oxidoreductase-gene-spanning-the-common-fragile-site-fra16d-in-multiple-myeloma-and-monoclonal-gammopathy-of-undetermined-significance
#5
Hiroshi Handa, Yoshiko Sasaki, Hikaru Hattori, Lobna Alkebsi, Tetsuhiro Kasamatsu, Takayuki Saitoh, Takeki Mitsui, Akihiko Yokohama, Norifumi Tsukamoto, Morio Matsumoto, Hirokazu Murakami
The putative tumor suppressor gene WW domain containing oxidoreductase (WWOX) spans a common fragile site (CFS) on chromosome 16q23.3. CFSs are regions of profound genomic instability and sites for genomic deletions in cancer cells. Therefore, WWOX is structurally altered in diverse nonhematological cancer types. However, the function of WWOX in hematological tumor types, including multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) remains unclear. WWOX expression and methylation in patients with MM, MGUS, or noninvasive lymphoma (control) were analyzed using reverse transcription- and methylation specific-polymerase chain reaction analysis...
October 2017: Oncology Letters
https://www.readbyqxmd.com/read/28943924/network-based-analysis-of-the-molecular-mechanisms-of-multiple-myeloma-and-monoclonal-gammopathy-of-undetermined-significance
#6
Zhi Liu, Jing Huang, Qi Zhong, Yanling She, Ruimin Ou, Cheng Li, Rui Chen, Mengdong Yao, Qing Zhang, Shuang Liu
The present study aimed to reveal the molecular mechanisms of multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS). This was a secondary study on microarray dataset GSE80608, downloaded from the Gene Expression Omnibus database, which included 10 control samples, 10 MGUS samples and 10 MM samples. Differentially expressed genes (DEGs) were identified between control and MGUS samples, and between control and MM samples. A protein-protein interaction (PPI) network was built for studying the interactions between the DEGs...
October 2017: Oncology Letters
https://www.readbyqxmd.com/read/28938542/the-immune-checkpoint-molecule-v-set-ig-domain-containing-4-is-an-independent-prognostic-factor-for-multiple-myeloma
#7
Jin Roh, Youkyoung Jeon, A-Neum Lee, Sang Min Lee, YeonMee Kim, Chang Ohk Sung, Chan-Jeoung Park, Jung Yong Hong, Dok Hyun Yoon, Cheolwon Suh, Jooryung Huh, Inhak Choi, Chan-Sik Park
Multiple myeloma (MM) remains as an incurable disease, despite recent substantial improvements in treatment. Therefore, development of novel biomarkers for risk stratification and new therapeutic targets are imperative. One of the emerging treatments for MM is the immune checkpoint blockades. V-set Ig domain-containing 4 (VSIG4) is a lately studied B7-related immune checkpoint modulator. We assessed the VSIG4 expression in patients with MM and its prognostic impact. We analyzed 81 bone marrow and 66 extramedullary biopsy samples of MM patients using immunohistochemistry...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28914853/-uromodulin-gene-polymorphisms-in-patients-with-cast-nephropathy-in-multiple-myeloma
#8
I G Rekhtina, L P Mendeleeva, B V Biderman, M V Solovyev, A B Sudarikov
AIM: To investigate the nature of mutations in exons 4 and 5 of the uromodulin (UM) gene, including in the area encoding the domain of 8 cysteines (D8C), in patients with multiple myeloma (MM) with the secretion of monoclonal light chains (LC) in cast nephropathy (CN) and without kidney injury. SUBJECTS AND METHODS: The investigation enrolled 24 patients in MM remission, who were observed to have monoclonal LC secretion at onset. Group 1 included 14 patients with CN; Group 2 consisted of 10 patients with normal renal function (a comparison group)...
2017: Terapevticheskiĭ Arkhiv
https://www.readbyqxmd.com/read/28903573/crispr-in-research-and-treatment-of-multiple-myeloma
#9
M M Simicek, K Growkova, R Hájek
In the recent years, there was a remarkable advance in research and clinical implementation of the genome editing technologies. The most remarkable was a discovery of the bacterial adaptive immune system called CRISPR and its rapid transformation into a robust and broadly applicable technology that completely revolutionized both basic and applied biomedical research. Implementation of CRISPR makes genome modification easier, faster and significantly cheaper compare to any other currently available technology...
2017: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
https://www.readbyqxmd.com/read/28903572/biomarkers-in-immunoglobulin-light-chain-amyloidosis
#10
Z Kufová, T Sevcikova, K Growkova, P Vojta, J Filipová, Z Adam, L Pour, M Penka, R Rysava, P Němec, L Brozova, P Vychytilova, A Jurczyszyn, S Grosicki, A Barchnicka, M Hajdúch, M Simicek, R Hájek
Immunoglobulin light chain amyloidosis (AL amyloidosis - ALA) is a monoclonal gammopathy characterized by presence of aberrant plasma cells producing amyloidogenic immunoglobulin light chains. This leads to formation of amyloid fibrils in various organs and tissues, mainly in heart and kidney, and causes their dysfunction. As amyloid depositing in target organs is irreversible, there is a big effort to identify biomarker that could help to distinguish ALA from other monoclonal gammopathies in the early stages of disease, when amyloid deposits are not fatal yet...
2017: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
https://www.readbyqxmd.com/read/28903037/genetic-predisposition-to-multiple-myeloma-at-5q15-is-mediated-by-an-ell2-enhancer-polymorphism
#11
Ni Li, David C Johnson, Niels Weinhold, Scott Kimber, Sara E Dobbins, Jonathan S Mitchell, Ben Kinnersley, Amit Sud, Philip J Law, Giulia Orlando, Matthew Scales, Christopher P Wardell, Asta Försti, Phuc H Hoang, Molly Went, Amy Holroyd, Fadi Hariri, Tomi Pastinen, Tobias Meissner, Hartmut Goldschmidt, Kari Hemminki, Gareth J Morgan, Martin Kaiser, Richard S Houlston
Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion...
September 12, 2017: Cell Reports
https://www.readbyqxmd.com/read/28878380/an-in-silico-approach-to-predict-and-exploit-synthetic-lethality-in-cancer-metabolism
#12
Iñigo Apaolaza, Edurne San José-Eneriz, Luis Tobalina, Estíbaliz Miranda, Leire Garate, Xabier Agirre, Felipe Prósper, Francisco J Planes
Synthetic lethality is a promising concept in cancer research, potentially opening new possibilities for the development of more effective and selective treatments. Here, we present a computational method to predict and exploit synthetic lethality in cancer metabolism. Our approach relies on the concept of genetic minimal cut sets and gene expression data, demonstrating a superior performance to previous approaches predicting metabolic vulnerabilities in cancer. Our genetic minimal cut set computational framework is applied to evaluate the lethality of ribonucleotide reductase catalytic subunit M1 (RRM1) inhibition in multiple myeloma...
September 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/28835615/logic-programming-reveals-alteration-of-key-transcription-factors-in-multiple-myeloma
#13
Bertrand Miannay, Stéphane Minvielle, Olivier Roux, Pierre Drouin, Hervé Avet-Loiseau, Catherine Guérin-Charbonnel, Wilfried Gouraud, Michel Attal, Thierry Facon, Nikhil C Munshi, Philippe Moreau, Loïc Campion, Florence Magrangeas, Carito Guziolowski
Innovative approaches combining regulatory networks (RN) and genomic data are needed to extract biological information for a better understanding of diseases, such as cancer, by improving the identification of entities and thereby leading to potential new therapeutic avenues. In this study, we confronted an automatically generated RN with gene expression profiles (GEP) from a cohort of multiple myeloma (MM) patients and normal individuals using global reasoning on the RN causality to identify key-nodes. We modeled each patient by his or her GEP, the RN and the possible automatically detected repairs needed to establish a coherent flow of the information that explains the logic of the GEP...
August 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28814763/spatial-genomic-heterogeneity-in-multiple-myeloma-revealed-by-multi-region-sequencing
#14
L Rasche, S S Chavan, O W Stephens, P H Patel, R Tytarenko, C Ashby, M Bauer, C Stein, S Deshpande, C Wardell, T Buzder, G Molnar, M Zangari, F van Rhee, S Thanendrarajan, C Schinke, J Epstein, F E Davies, B A Walker, T Meissner, B Barlogie, G J Morgan, N Weinhold
In multiple myeloma malignant plasma cells expand within the bone marrow. Since this site is well-perfused, a rapid dissemination of "fitter" clones may be anticipated. However, an imbalanced distribution of multiple myeloma is frequently observed in medical imaging. Here, we perform multi-region sequencing, including iliac crest and radiology-guided focal lesion specimens from 51 patients to gain insight into the spatial clonal architecture. We demonstrate spatial genomic heterogeneity in more than 75% of patients, including inactivation of CDKN2C and TP53, and mutations affecting mitogen-activated protein kinase genes...
August 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/28806822/-multiple-myeloma-current-status-in-diagnostic-testing-and-therapy
#15
Michael Kehrer, Sebastian Koob, Andreas Strauss, Dieter Christian Wirtz, Jan Schmolders
Background Multiple myeloma is a haematological blood cancer of the bone marrow and is classified by the World Health Organisation (WHO) as a plasma cell neoplasm. In multiple myeloma, normal plasma cells transform into malignant myeloma cells and produce large quantities of an abnormal immunoglobulin called monoclonal protein or M protein. This ultimately causes multiple myeloma symptoms such as bone damage or kidney problems. The annual worldwide incidence of multiple myeloma is estimated to be 6 - 7/100,000 and accounts for 1% of all cancer...
October 2017: Zeitschrift Für Orthopädie und Unfallchirurgie
https://www.readbyqxmd.com/read/28760306/high-risk-multiple-myeloma-definition-and-management
#16
REVIEW
Nisha S Joseph, Silvia Gentili, Jonathan L Kaufman, Sagar Lonial, Ajay K Nooka
The prognosis of patients with multiple myeloma has significantly improved after the introduction of novel concepts of immunomodulation and proteasome inhibition in myeloma therapies. In conjunction with the use of high-dose therapy and autologous stem cell transplantation, these newer antimyeloma agents facilitated the augmentation of deeper responses and as a result, enhanced survival outcomes. Despite mounting clinical evidence that novel therapies may mitigate the poor prognostic impact of some predictors historically considered "harbingers of doom" in myeloma such as t(4;14), the benefit of these advances is less evident in patients who present with genetically defined high-risk features such as presence of chromosomal abnormalities del17p, t(14;16), or t(14;20), or among patients presenting with plasma cell leukemia...
July 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28729121/multiple-myeloma-genomics-a-systematic-review
#17
REVIEW
Casey J Weaver, Joseph D Tariman
OBJECTIVES: This integrative review describes the genomic variants that have been found to be associated with poor prognosis in patients diagnosed with multiple myeloma (MM). Second, it identifies MM genetic and genomic changes using next-generation sequencing, specifically whole-genome sequencing or exome sequencing. DATA SOURCE: A search for peer-reviewed articles through PubMed, EBSCOhost, and DePaul WorldCat Libraries Worldwide yielded 33 articles that were included in the final analysis...
August 2017: Seminars in Oncology Nursing
https://www.readbyqxmd.com/read/28698358/integrative-cage-and-dna-methylation-profiling-identify-epigenetically-regulated-genes-in-nsclc
#18
Masafumi Horie, Bogumil Kaczkowski, Mitsuhiro Ohshima, Hirotaka Matsuzaki, Satoshi Noguchi, Yu Mikami, Marina Lizio, Masayoshi Itoh, Hideya Kawaji, Timo Lassmann, Piero Carninci, Yoshihide Hayashizaki, Alistair R R Forrest, Daiya Takai, Yoko Yamaguchi, Patrick Micke, Akira Saito, Takahide Nagase
Lung cancer is the leading cause of cancer-related deaths worldwide. The majority of cancer driver mutations have been identified; however, relevant epigenetic regulation involved in tumorigenesis has only been fragmentarily analyzed. Epigenetically regulated genes have a great theranostic potential, especially in tumors with no apparent driver mutations. Here, epigenetically regulated genes were identified in lung cancer by an integrative analysis of promoter-level expression profiles from Cap Analysis of Gene Expression (CAGE) of 16 non-small cell lung cancer (NSCLC) cell lines and 16 normal lung primary cell specimens with DNA methylation data of 69 NSCLC cell lines and 6 normal lung epithelial cells...
July 11, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28691553/the-adverse-effect-of-fopnl-genomic-variant-is-reversed-by-bortezomib-based-treatment-protocols-in-multiple-myeloma
#19
Katalin Piroska Kiss, Gergely Varga, Gabor Mikala, Katalin Balassa, Andras Bors, Petra Kovy, Nora Meggyesi, Andras Kozma, Otto Csacsovszki, Peter Remenyi, Istvan Valyi-Nagy, Attila Tordai, Tamas Masszi, Hajnalka Andrikovics
Fibroblast growth factor receptor 1 oncogene partner N-terminal like gene (FOPNL) rs72773978 polymorphism was identified as an adverse prognostic factor in multiple myeloma (MM). We aimed to investigate the associations of rs72773978 with clinical characteristics and treatment outcome in 373 Hungarian MM patients. In our cohort, FOPNL polymorphism showed differential prognostic effect that depended on the treatment applied. Among patients treated with non-proteasome inhibitor (PI)-based therapy, carriership of the minor allele was significantly associated with adverse overall survival (p=...
July 9, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28669490/ilf2-is-a-regulator-of-rna-splicing-and-dna-damage-response-in-1q21-amplified-multiple-myeloma
#20
Matteo Marchesini, Yamini Ogoti, Elena Fiorini, Anil Aktas Samur, Luigi Nezi, Marianna D'Anca, Paola Storti, Mehmet Kemal Samur, Irene Ganan-Gomez, Maria Teresa Fulciniti, Nipun Mistry, Shan Jiang, Naran Bao, Valentina Marchica, Antonino Neri, Carlos Bueso-Ramos, Chang-Jiun Wu, Li Zhang, Han Liang, Xinxin Peng, Nicola Giuliani, Giulio Draetta, Karen Clise-Dwyer, Hagop Kantarjian, Nikhil Munshi, Robert Orlowski, Guillermo Garcia-Manero, Ronald A DePinho, Simona Colla
Amplification of 1q21 occurs in approximately 30% of de novo and 70% of relapsed multiple myeloma (MM) and is correlated with disease progression and drug resistance. Here, we provide evidence that the 1q21 amplification-driven overexpression of ILF2 in MM promotes tolerance of genomic instability and drives resistance to DNA-damaging agents. Mechanistically, elevated ILF2 expression exerts resistance to genotoxic agents by modulating YB-1 nuclear localization and interaction with the splicing factor U2AF65, which promotes mRNA processing and the stabilization of transcripts involved in homologous recombination in response to DNA damage...
July 10, 2017: Cancer Cell
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