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Myeloma genomics

Aurore Perrot, Jill Corre, Hervé Avet-Loiseau
In the past 15 years, significant improvements in overall survival have been observed in multiple myeloma (MM), mainly due to the availability of novel drugs with variable mechanisms of action. However, these improvements do not benefit all patients, and some of them, defined as high risk, still display short survival. The most important risk factors are the genetic abnormalities present in the malignant plasma cells. The most important high-risk features are the del(17p), the del(1p32), the t(4;14), and 1q gains...
May 23, 2018: American Society of Clinical Oncology Educational Book
Pasquale L Fedele, Simon N Willis, Yang Liao, Michael S Low, Jai Rautela, David H Segal, Jia-Nan Gong, Nicholas D Huntington, Wei Shi, David C S Huang, George Grigoriadis, Julie Tellier, Stephen L Nutt
Recent studies have demonstrated that the immunomodulatory drugs (IMiDs) lead to the degradation of the transcription factors Ikaros and Aiolos. However, why their loss subsequently leads to multiple myeloma (MM) cell death remains unclear. Using CRISPR-Cas9 genome editing, we have deleted IKZF1/Ikaros and IKZF3/Aiolos in human MM cell lines to gain further insight into their downstream gene regulatory networks. Inactivation of either factor alone recapitulates the cell intrinsic action of the IMiDs, resulting in cell cycle arrest and induction of apoptosis...
September 18, 2018: Blood
Molly Went, Amit Sud, Asta Försti, Britt-Marie Halvarsson, Niels Weinhold, Scott Kimber, Mark van Duin, Gudmar Thorleifsson, Amy Holroyd, David C Johnson, Ni Li, Giulia Orlando, Philip J Law, Mina Ali, Bowang Chen, Jonathan S Mitchell, Daniel F Gudbjartsson, Rowan Kuiper, Owen W Stephens, Uta Bertsch, Peter Broderick, Chiara Campo, Obul R Bandapalli, Hermann Einsele, Walter A Gregory, Urban Gullberg, Jens Hillengass, Per Hoffmann, Graham H Jackson, Karl-Heinz Jöckel, Ellinor Johnsson, Sigurður Y Kristinsson, Ulf-Henrik Mellqvist, Hareth Nahi, Douglas Easton, Paul Pharoah, Alison Dunning, Julian Peto, Federico Canzian, Anthony Swerdlow, Rosalind A Eeles, ZSofia Kote-Jarai, Kenneth Muir, Nora Pashayan, Jolanta Nickel, Markus M Nöthen, Thorunn Rafnar, Fiona M Ross, Miguel Inacio da Silva Filho, Hauke Thomsen, Ingemar Turesson, Annette Vangsted, Niels Frost Andersen, Anders Waage, Brian A Walker, Anna-Karin Wihlborg, Annemiek Broyl, Faith E Davies, Unnur Thorsteinsdottir, Christian Langer, Markus Hansson, Hartmut Goldschmidt, Martin Kaiser, Pieter Sonneveld, Kari Stefansson, Gareth J Morgan, Kari Hemminki, Björn Nilsson, Richard S Houlston
Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism...
September 13, 2018: Nature Communications
Giulia Biancon, Silvia Gimondi, Antonio Vendramin, Cristiana Carniti, Paolo Corradini
Novel treatments for multiple myeloma (MM) have increased rates of complete response, raising interest in more accurate methods to evaluate residual disease. Cell-free tumor DNA (cfDNA) analysis may represent a minimally invasive approach complementary to multiparameter flow cytometry (MFC) and molecular methods on bone marrow aspirates. A sequencing approach using the Ion Torrent Personal Genome Machine was applied to identify clonal IGH gene rearrangements in tumor plasma cells (PCs) and in serial plasma samples of 25 patients with MM receiving second-line therapy...
August 28, 2018: Journal of Molecular Diagnostics: JMD
Niccolò Bolli, Francesco Maura, Stephane Minvielle, Dominik Gloznik, Raphael Szalat, Anthony Fullam, Inigo Martincorena, Kevin J Dawson, Mehmet Kemal Samur, Jorge Zamora, Patrick Tarpey, Helen Davies, Mariateresa Fulciniti, Masood A Shammas, Yu Tzu Tai, Florence Magrangeas, Philippe Moreau, Paolo Corradini, Kenneth Anderson, Ludmil Alexandrov, David C Wedge, Herve Avet-Loiseau, Peter Campbell, Nikhil Munshi
We analyzed whole genomes of unique paired samples from smoldering multiple myeloma (SMM) patients progressing to multiple myeloma (MM). We report that the genomic landscape, including mutational profile and structural rearrangements at the smoldering stage is very similar to MM. Paired sample analysis shows two different patterns of progression: a "static progression model", where the subclonal architecture is retained as the disease progressed to MM suggesting that progression solely reflects the time needed to accumulate a sufficient disease burden; and a "spontaneous evolution model", where a change in the subclonal composition is observed...
August 22, 2018: Nature Communications
Subhayan Chattopadhyay, Hauke Thomsen, Miguel Inacio da Silva Filho, Niels Weinhold, Per Hoffmann, Markus M Nöthen, Arendt Marina, Karl-Heinz Jöckel, Börge Schmidt, Sonali Pechlivanis, Christian Langer, Hartmut Goldschmidt, Kari Hemminki, Asta Försti
BACKGROUND: Recent identification of 10 germline variants predisposing to monoclonal gammopathy of undetermined significance (MGUS) explicates genetic dependency of this asymptomatic precursor condition with multiple myeloma (MM). Yet much of genetic burden as well as functional links remain unexplained. We propose a workflow to expand the search for susceptibility loci with genome-wide interaction and for subsequent identification of genetic clusters and pathways. METHODS: Polygenic interaction analysis on 243 cases/1285 controls identified 14 paired risk loci belonging to unique chromosomal bands which were then replicated in two independent sets (case only study, 82 individuals; case/control study 236 cases/ 2484 controls)...
June 11, 2018: Molecular Medicine
Mette Dahl, Lasse Sommer Kristensen, Kirsten Grønbæk
With the introduction of next generation sequencing methods, such as RNA sequencing, it has become apparent that alterations in the non-coding regions of our genome are important in the development of cancer. Particularly interesting is the class of long non-coding RNAs (lncRNAs), including the recently described subclass of circular RNAs (circRNAs), which display tissue- and cell-type specific expression patterns and exert diverse regulatory functions in the cells. B-cells undergo complex and tightly regulated processes in order to develop from antigen naïve cells residing in the bone marrow to the highly diverse and competent effector cells circulating in peripheral blood...
August 21, 2018: International Journal of Molecular Sciences
Ziyan Wang, Yuqing Yuan, Liying Zhang, Zhou Min, Dongming Zhou, Sun Yu, Panjun Wang, Songguang Ju, Li Jun, Jinxiang Fu
Background: Mesenchymal stem cells (MSCs) represent a subset of non-hematopoietic adult stem cells, which can also fuse with other cells spontaneously in bone marrow and capable of adopting the phenotype of other cells. The fusion of somatic cells with stem cells can reprogram somatic cells to a pluripotent state. Our research on the fusion of bone marrow mesenchymal stem cells(BM-MSCs) and MM cells demonstrate that the fused cells can exhibit stemness and cancer cell-like characteristics...
July 24, 2018: Oncotarget
Daniele Caracciolo, Maria Teresa Di Martino, Nicola Amodio, Eugenio Morelli, Martina Montesano, Cirino Botta, Francesca Scionti, Daniela Talarico, Emanuela Altomare, Maria Eugenia Gallo Cantafio, Valeria Zuccalà, Lorenza Maltese, Katia Todoerti, Marco Rossi, Mariamena Arbitrio, Antonino Neri, Pierosandro Tagliaferri, Pierfrancesco Tassone
Multiple myeloma (MM) is a hematologic malignancy characterized by high genomic instability. Here we provide evidence that hyper-activation of DNA ligase III (LIG3) is crucial for genomic instability and survival of MM cells. LIG3 mRNA expression in MM patients correlates with shorter survival and even increases with more advanced stage of disease. Knockdown of LIG3 impairs MM cells viability in vitro and in vivo, suggesting that neoplastic plasmacells are dependent on LIG3-driven repair. To investigate the mechanisms involved in LIG3 expression, we investigated the post-transcriptional regulation...
August 17, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Seyed Hamidreza Mahmoudpour, Obul Reddy Bandapalli, Miguel Inácio da Silva Filho, Chiara Campo, Kari Hemminki, Hartmut Goldschmidt, Maximilian Merz, Asta Försti
BACKGROUND: Based on the possible shared mechanisms of chemotherapy-induced peripheral neuropathy (CIPN) for different drugs, we aimed to aggregate results of all previously published genome-wide association studies (GWAS) on CIPN, and to replicate them within a cohort of multiple myeloma (MM) patients. METHODS: Following a systematic literature search, data for CIPN associated single nucleotide polymorphisms (SNPs) with P-values< 10- 5 were extracted; these associations were investigated within a cohort of 983 German MM patients treated with bortezomib, thalidomide or vincristine...
August 15, 2018: BMC Cancer
Szabolcs Kosztolanyi, Richard Kiss, Lilit Atanesyan, Ambrus Gango, Karel de Groot, Maryvonne Steenkamer, Pal Jakso, Andras Matolcsy, Bela Kajtar, Laszlo Pajor, Karoly Szuhai, Suvi Savola, Csaba Bodor, Donat Alpar
Multiple myeloma (MM) is a genetically heterogeneous disease with a diverse clinical outcome. Copy number alterations (CNAs), including whole chromosome and subchromosomal gains and losses, are common contributors of the pathogenesis and have demonstrated prognostic impact in MM. We tested the performance of digital multiplex ligation-dependent probe amplification (digitalMLPA), a novel technique combining MLPA and next-generation sequencing, to detect disease-related CNAs. Copy number status at 371 genomic loci was simultaneously analyzed in 56 diagnostic bone marrow samples, which were also examined by conventional MLPA and interphase fluorescence in situ hybridization (iFISH)...
August 8, 2018: Journal of Molecular Diagnostics: JMD
P Leif Bergsagel, W Michael Kuehl
No abstract text is available yet for this article.
August 9, 2018: Blood
Mette Dahl, Iben Daugaard, Maria Schertz Andersen, Thomas Birkballe Hansen, Kirsten Grønbæk, Jørgen Kjems, Lasse Sommer Kristensen
Circular RNAs (circRNAs) are covalently closed endogenous molecules with tissue- and disease-specific expression patterns, which have potential as diagnostic and prognostic biomarkers in cancer. The molecules are formed by a backsplicing event linking the 3'-end of an exon to the 5'-end of the same or an upstream exon, and they exert diverse regulatory functions important in carcinogenesis. The landscape of circRNA expression has not been characterized in B-cell malignancies, and current methods for circRNA quantification have several limitations that prevent development of clinically applicable assays...
August 7, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
Quinlan L Sievers, Jessica A Gasser, Glenn S Cowley, Eric S Fischer, Benjamin L Ebert
Lenalidomide mediates the ubiquitination and degradation of IKZF1, IKZF3 and CK1α by facilitating their interaction with cereblon (CRBN), the substrate receptor for the CRL4CRBN E3 ubiquitin ligase. Through this mechanism, lenalidomide is a clinically effective treatment for multiple myeloma and myelodysplastic syndrome with deletion of chromosome 5q (del(5q) MDS). To identify the cellular machinery required for lenalidomide-induced CRL4CRBN activity, we performed a positive selection, genome-scale CRISPR-Cas9 screen in a lenalidomide-sensitive myeloma cell line...
July 24, 2018: Blood
Jiye Liu, Tianyu Song, Wenrong Zhou, Lijie Xing, Su Wang, Matthew Ho, Zhengang Peng, Yu-Tzu Tai, Teru Hideshima, Kenneth C Anderson, Yong Cang
Immunomodulatory drugs (IMiDs) including lenalidomide and pomalidomide bind cereblon (CRBN) and activate the CRL4CRBN ubiquitin ligase to trigger proteasomal degradation of the essential transcription factors IKZF1 and IKZF3 and multiple myeloma (MM) cytotoxicity. We have shown that CRBN is also targeted for degradation by SCFFbxo7 ubiquitin ligase. In the current study, we explored the mechanisms underlying sensitivity of MM cells to IMiDs using genome-wide CRISPR-Cas9 screening. We validate that CSN9 signalosome complex, a deactivator of Cullin-RING ubiquitin ligase, inhibits SCFFbxo7 E3 ligase-mediated CRBN degradation, thereby conferring sensitivity to IMiDs; conversely, loss of function of CSN9 signalosome activates SCFFbxo7 complex, thereby enhancing degradation of CRBN and conferring IMiD resistance...
July 19, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Wolfgang Willenbacher, Andreas Seeber, Normann Steiner, Ella Willenbacher, Zoran Gatalica, Jeff Swensen, Jeffery Kimbrough, Semir Vranic
Multiple myeloma (MM), the second most common hematologic malignancy, is characterized by the clonal expansion of plasma cells. Despite dramatic improvements in patients' survival over the past decade due to advances in therapy exploiting novel molecular targets (immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies), the treatment of relapsed and refractory disease remains challenging. Recent studies confirmed complex, dynamic, and heterogeneous genomic alterations without unifying gene mutations in MM patients...
July 18, 2018: International Journal of Molecular Sciences
Susu Han, Tao Huang, Wen Li, Shanshan Liu, Wei Yang, Qi Shi, Hongjia Li, Jianlin Ren, Fenggang Hou
BACKGROUND/AIMS: Although some studies showed that HIF-2α expression was correlated with an unfavorable prognosis in colorectal cancer (CRC), the prognostic results remain conflicting in CRC. The present study was performed to evaluate the association between HIF-2α expression and the clinicopathological features of this disease and to examine the potential prognostic role of HIF-2α expression in CRC. METHODS: Pooled odds ratios (ORs) or hazard ratios (HRs) were calculated from available publications, The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) datasets...
2018: Cellular Physiology and Biochemistry
Martin Bommer, Miriam Kull, Veronica Teleanu, Phyllis Schwarzwälder, Manuela Feuring-Buske, Jan Kroenke, Donald Bunjes, Christian Langer
INTRODUCTION: Involvement of the central nervous system in patients with multiple myeloma is a rare event. We evaluated the diagnostic workup and prognosis of patients with leptomeningeal myelomatosis (LMM). METHODS: Between April 2005 and April 2016, we identified 16 cases with LMM. The involvement was diagnosed by magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) cytology as well as flow cytometry. Fluorescence in situ hybridization (FISH) was used in 8/16 cases...
2018: Acta Haematologica
Yen-Chien Lee, Chung-Cheng Hsieh, Yen-Ling Lee, Chung-Yi Li
Molecular markers are important in guiding treatment and predicting outcome in the genomic era. Meta-analysis of molecular markers in myelofibrosis through a search of PubMed and Medline through October 31, 2017 was performed. Markers with more than 3 studies that compared overall survival (OS) and leukemia-free survival (LFS) were analyzed. A total of 16 studies were included. Hazard ratios (HRs) for OS were as follows: IDH 2.65 (95% confidence interval [CI], 1.66-4.21), SRSF2 2.12 (95% CI, 1.18-3.79), high-risk myeloma 2...
September 2018: Clinical Lymphoma, Myeloma & Leukemia
Brian A Walker, Konstantinos Mavrommatis, Christopher P Wardell, T Cody Ashby, Michael Bauer, Faith Davies, Adam Rosenthal, Hongwei Wang, Pingping Qu, Antje Hoering, Mehmet Samur, Fadi Towfic, Maria Ortiz, Erin Flynt, Zhinuan Yu, Zhihong Yang, Dan Rozelle, John Obenauer, Matthew Trotter, Daniel Auclair, Jonathan Keats, Niccolo Bolli, Mariateresa Fulciniti, Raphael Szalat, Phillipe Moreau, Brian Durie, A Keith Stewart, Hartmut Goldschmidt, Marc S Raab, Hermann Einsele, Pieter Sonneveld, Jesus San Miguel, Sagar Lonial, Graham H Jackson, Kenneth C Anderson, Herve Avet-Loiseau, Nikhil Munshi, Anjan Thakurta, Gareth Morgan
Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior...
July 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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