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https://www.readbyqxmd.com/read/28504647/identification-of-a-nucleoside-analog-active-against-adenosine-kinase-expressing-plasma-cell-malignancies
#1
Utthara Nayar, Jouliana Sadek, Jonathan Reichel, Denise Hernandez-Hopkins, Gunkut Akar, Peter J Barelli, Michelle A Sahai, Hufeng Zhou, Jennifer Totonchy, David Jayabalan, Ruben Niesvizky, Ilaria Guasparri, Duane Hassane, Yifang Liu, Shizuko Sei, Robert H Shoemaker, J David Warren, Olivier Elemento, Kenneth M Kaye, Ethel Cesarman
Primary effusion lymphoma (PEL) is a largely incurable malignancy of B cell origin with plasmacytic differentiation. Here, we report the identification of a highly effective inhibitor of PEL. This compound, 6-ethylthioinosine (6-ETI), is a nucleoside analog with toxicity to PEL in vitro and in vivo, but not to other lymphoma cell lines tested. We developed and performed resistome analysis, an unbiased approach based on RNA sequencing of resistant subclones, to discover the molecular mechanisms of sensitivity...
May 15, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28490465/dual-inhibition-of-ezh2-and-ezh1-sensitizes-prc2-dependent-tumors-to-proteasome-inhibition
#2
Ola Rizq, Naoya Mimura, Motohiko Oshima, Atsunori Saraya, Shuhei Koide, Yuko Kato, Kazumasa Aoyama, Yaeko Nakajima-Takagi, Changshan Wang, Tetsuhiro Chiba, Anqi Ma, Jian Jin, Tohru Iseki, Chiaki Nakaseko, Atsushi Iwama
<br /> <p>EZH2 and EZH1, the catalytic components of polycomb repressive complex 2 (PRC2), trigger trimethylation of H3K27 (H3K27me3) to repress the transcription of target genes and are implicated in the pathogenesis of various cancers including multiple myeloma (MM) and prostate cancer. Here, we investigated the preclinical effects of UNC1999, a dual inhibitor of EZH2 and EZH1, in combination with proteasome inhibitors on MM and prostate cancer.</p> <br /><br />Experimental Design: <br /> <p>In vitro and in vivo efficacy of UNC1999 and the combination with proteasome inhibitors was evaluated in MM cell lines, primary patient cells and in a xenograft model...
May 10, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28487543/kdm6b-modulates-mapk-pathway-mediating-multiple-myeloma-cell-growth-and-survival
#3
H Ohguchi, T Harada, M Sagawa, S Kikuchi, Y-T Tai, P G Richardson, T Hideshima, K C Anderson
Recent studies have delineated cancer type-specific roles of histone 3 lysine 27 (H3K27) demethylase KDM6B/JMJD3 depending on its H3K27 demethylase activity. Here we show that KDM6B is expressed in multiple myeloma (MM); and that shRNA-mediated knockdown and CRISPR-mediated knockout of KDM6B abrogate MM cell growth and survival. TNFα or bone marrow stromal cell culture supernatants induce KDM6B, which is blocked by IKKβ inhibitor MLN120B, suggesting KDM6B is regulated by NF-κB signaling in MM cells. RNA-sequencing and subsequent ChIP-qPCR analyses reveal that KDM6B is recruited to the loci of genes encoding components of MAPK signaling pathway including ELK1 and FOS, and upregulates these genes expression without affecting H3K27 methylation level...
May 10, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28439108/phase-i-trial-of-systemic-administration-of-edmonston-strain-of-measles-virus-genetically-engineered-to-express-the-sodium-iodide-symporter-in-patients-with-recurrent-or-refractory-multiple-myeloma
#4
A Dispenzieri, C Tong, B LaPlant, M Q Lacy, K Laumann, D Dingli, Y Zhou, M J Federspiel, M A Gertz, S Hayman, F Buadi, M O'Connor, V J Lowe, K-W Peng, S J Russell
MV-NIS is an Edmonston-lineage oncolytic measles virus expressing the human sodium-iodide symporter--a means for monitoring by noninvasive imaging of radioiodine. Patients with relapsed, refractory myeloma who had explored all other treatment options were eligible for this Phase I trial. Cohort 1 was treated with intravenous MV-NIS, and Cohort 2 received cyclophosphamide two days prior to MV-NIS. Thirty-two patients were treated. Cohort 1 initially enrolled to 4 dose-levels without reaching MTD and subsequently to 2 higher dose-levels when improved virus manufacture technology made it possible...
April 25, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28420429/deptor-maintains-plasma-cell-differentiation-and-favorably-affects-prognosis-in-multiple-myeloma
#5
Dalia Quwaider, Luis A Corchete, Irena Misiewicz-Krzeminska, María E Sarasquete, José J Pérez, Patryk Krzeminski, Noemí Puig, María Victoria Mateos, Ramón García-Sanz, Ana B Herrero, Norma C Gutiérrez
BACKGROUND: The B cell maturation process involves multiple steps, which are controlled by relevant pathways and transcription factors. The understanding of the final stages of plasma cell (PC) differentiation could provide new insights for therapeutic strategies in multiple myeloma (MM). Here, we explore the role of DEPTOR, an mTOR inhibitor, in the terminal differentiation of myeloma cells, and its potential impact on patient survival. METHODS: The expression level of DEPTOR in MM cell lines and B cell populations was measured by real-time RT-PCR, and/or Western blot analysis...
April 18, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28378636/potential-prognostic-long-non-coding-rna-identification-and-their-validation-in-predicting-survival-of-patients-with-multiple-myeloma
#6
Ai-Xin Hu, Zhi-Yong Huang, Lin Zhang, Jian Shen
Multiple myeloma, a typical hematological malignancy, is characterized by malignant proliferation of plasma cells. This study was to identify differently expressed long non-coding RNAs to predict the survival of patients with multiple myeloma efficiently. Gene expressing profiles of diagnosed patients with multiple myeloma, GSE24080 (559 samples) and GSE57317 (55 samples), were downloaded from Gene Expression Omnibus database. After processing, survival-related long non-coding RNAs were identified by Cox regression analysis...
April 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28369725/rna-polymerase-i-inhibition-with-cx-5461-as-a-novel-therapeutic-strategy-to-target-myc-in-multiple-myeloma
#7
Hans C Lee, Hua Wang, Veerabhadran Baladandayuthapani, Heather Lin, Jin He, Richard J Jones, Isere Kuiatse, Dongmin Gu, Zhiqiang Wang, Wencai Ma, John Lim, Sean O'Brien, Jonathan Keats, Jing Yang, Richard E Davis, Robert Z Orlowski
Dysregulation of MYC is frequently implicated in both early and late myeloma progression events, yet its therapeutic targeting has remained a challenge. Among key MYC downstream targets is ribosomal biogenesis, enabling increases in protein translational capacity necessary to support the growth and self-renewal programmes of malignant cells. We therefore explored the selective targeting of ribosomal biogenesis with the small molecule RNA polymerase (pol) I inhibitor CX-5461 in myeloma. CX-5461 induced significant growth inhibition in wild-type (WT) and mutant TP53 myeloma cell lines and primary samples, in association with increases in downstream markers of apoptosis...
April 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28360189/biobanking-strategy-and-sample-preprocessing-for-integrative-research-in-monoclonal-gammopathies
#8
T Ševčíková, K Growková, Z Kufová, J Filipová, P Vrublová, T Jelínek, Z Kořístek, F Kryukov, E Kryukova, R Hájek
AIMS: Some types of monoclonal gammopathies are typified by a very limited availability of aberrant cells. Modern research use high throughput technologies and an integrated approach for detailed characterisation of abnormal cells. This strategy requires relatively high amounts of starting material which cannot be obtained from every diagnosis without causing inconvenience to the patient. The aim of this methodological paper is to reflect our long experience with laboratory work and describe the best protocols for sample collection, sorting and further preprocessing in terms of the available number of cells and intended downstream application in monoclonal gammopathies research...
March 30, 2017: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/28359248/immunomodulatory-activity-of-micrornas-potential-implications-for-multiple-myeloma-treatment
#9
Cirino Botta, Maria Cucè, Daniele Caracciolo, Lucia Fiorillo, Pierosandro Tagliaferri, Pierfrancesco Tassone
Multiple myeloma (MM) is an incurable plasma cell neoplasm accounting for about 10% of all hematologic malignancies. Recently, emerging evidence is disclosing the complexity of bone marrow interactions between MM cells and infiltrating immune cells, which have been reported to promote proliferation, survival and drug resistance of tumor cells. MicroRNAs (miRNAs) are small non-coding RNA molecules with regulatory functions in the cell, whose expression has predictive and prognostic value in different malignancies...
March 30, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28341836/fam46c-is-critical-for-the-anti-proliferation-and-pro-apoptotic-effects-of-norcantharidin-in-hepatocellular-carcinoma-cells
#10
Qiao-Yan Zhang, Xiao-Qiang Yue, Yi-Ping Jiang, Ting Han, Hai-Liang Xin
Norcantharidin (NCTD), a demethylated analog of cantharidin derived from Chinese traditional medicine blister beetle, has been currently used as an anticancer drug for various cancers including hepatocellular carcinoma (HCC). In this study, for a more comprehensive understanding of the targets of NCTD in HCC, next-generation RNA-Seq was utilized. We revealed that the expression of FAM46C, which has been reported as a tumor suppressor for multiple myeloma, was enhanced after NCTD treatment. Re-analysis of TCGA (The Cancer Genome Atlas) LIHC (liver hepatocellular carcinoma) dataset demonstrated that FAM46C expression was significantly lower in HCC tissues than in normal liver tissues...
March 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28338204/nsd2-promotes-osteosarcoma-cell-proliferation-and-metastasis-by-inhibiting-e-cadherin-expression
#11
M-H Lu, M-F Fan, X-D Yu
OBJECTIVE: Osteosarcoma is one of the most common malignant bone tumors. The mechanisms of osteosarcoma development and invasion have been studied for periods of time, yet targeted therapy for improving survival has not been well established. Histone lysine methyltransferase NSD2 was frequently overexpressed in multiple types of cancer such as multiple myeloma, stomach and colon cancer, and the overexpression of it usually associated with aggressiveness tumor type. However, the expression status and function of NSD2 are still ambiguous in osteosarcoma...
March 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28325354/solitary-plasmacytoma-associated-with-epstein-barr-virus-a-clinicopathologic-cytogenetic-study-and-literature-review
#12
Jiaqi Yan, Jianchao Wang, Wenyan Zhang, Min Chen, Jie Chen, Weiping Liu
Solitary plasmacytoma (SP) is an uncommon, indolent tumor of plasma cell neoplasms that presents as a mass lesion in extramedullary sites. Evidence of Epstein-Barr virus (EBV) infection is frequently associated with various lymphatic and hematopoietic malignancies but is relatively rare in SP. Moreover, it is essential to distinguish EBV-positive plasmacytoma from plasmablastic lymphoma. In this study, we found 4 EBV-encoded RNA (EBER)-positive patients among 46 consecutive immunocompetent patients of SP and compared the clinicopathologic features of these patients with those of the EBER-negative cohort...
April 2017: Annals of Diagnostic Pathology
https://www.readbyqxmd.com/read/28282033/pi3k%C3%AE-and-pi3k%C3%AE-isoforms-have-distinct-functions-in-regulating-pro-tumoural-signalling-in-the-multiple-myeloma-microenvironment
#13
R E Piddock, N Loughran, C R Marlein, S D Robinson, D R Edwards, S Yu, G E Pillinger, Z Zhou, L Zaitseva, M J Auger, S A Rushworth, K M Bowles
Phosphoinositide-3-kinase and protein kinase B (PI3K-AKT) is upregulated in multiple myeloma (MM). Using a combination of short hairpin RNA (shRNA) lentivirus-mediated knockdown and pharmacologic isoform-specific inhibition we investigated the role of the PI3K p110γ (PI3Kγ) subunit in regulating MM proliferation and bone marrow microenvironment-induced MM interactions. We compared this with inhibition of the PI3K p110δ (PI3kδ) subunit and with combined PI3kδ/γ dual inhibition. We found that MM cell adhesion and migration were PI3Kγ-specific functions, with PI3kδ inhibition having no effect in MM adhesion or migration assays...
March 10, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28276319/long-non-coding-rna-crnde-promotes-multiple-myeloma-cell-growth-by-suppressing-mir-451
#14
Yi-Bin Meng, Xin He, Yun-Fei Huang, Qi-Ning Wu, Yong-Cun Zhou, Ding-Jun Hao
Long non-coding RNAs (lncRNAs) have been determinately identified as potential regulatory factor in multiple tumors, aswell as multiple myeloma (MM). However, the role of colorectal neoplasia differentially expressed (CRNDE) in pathogenesis of MM remains unclear. In this study, we found that the CRNDE expression level, in MM sample and cell lines, is higher than control detected by real-time qPCR, which is also closely related to tumor progression and poor survival in MM patients. Afterwards, knockdown of CRNDE significantly inhibits the proliferative vitality of MM cells (U266 and RPMI8226), meanwhile, induces cell cycle arrest in G0/G1 phase and apoptosis-promoting...
March 9, 2017: Oncology Research
https://www.readbyqxmd.com/read/28264449/tumor-cell-derived-microvesicles-induced-not-epithelial-mesenchymal-transition-but-apoptosis-in-human-proximal-tubular-hk-2-cells-implications-for-renal-impairment-in-multiple-myeloma
#15
Aiqi Zhao, Fancong Kong, Chun-Jie Liu, Guoxin Yan, Fei Gao, Hao Guo, An-Yuan Guo, Zhichao Chen, Qiubai Li
Renal impairment (RI) is one of the hallmarks of multiple myeloma (MM) and carries a poor prognosis. Microvesicles (MVs) are membrane vesicles and play an important role in disease progression. Here, we investigated the role of MVs derived from MM cells (MM-MVs) in RI of MM. We found that MM-MVs significantly inhibited viability and induced apoptosis, but not epithelial-mesenchymal transition in human kidney-2 (HK-2), a human renal tubular epithelial cell line. The protein levels of cleaved caspase-3, 8, and 9, and E-cadherin, were increased, but vementin levels were decreased in the HK-2 cells treated with MM-MVs...
February 27, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28256509/customized-laboratory-tlr4-and-tlr2-detection-method-from-peripheral-human-blood-for-early-detection-of-doxorubicin-induced-cardiotoxicity
#16
A L Pop-Moldovan, N-M Trofenciuc, D A Dărăbanţiu, C Precup, H Branea, R Christodorescu, M Puşchiţă
Cancer treatments can have significant cardiovascular adverse effects that can cause cardiomyopathy and heart failure with reduced survival benefit and considerable decrease in the use of antineoplastic therapy. The purpose of this study is to assess the role of TLR2 and TLR4 gene expression as an early marker for the risk of doxorubicin-induced cardiomyopathy in correlation with early diastolic dysfunction in patients treated with doxorubicin. Our study included 25 consecutive patients who received treatment with doxorubicin for hematological malignancies (leukemia, lymphomas or multiple myeloma), aged 18-65 years, with a survival probability>6 months and with left ventricular ejection fraction>50%...
May 2017: Cancer Gene Therapy
https://www.readbyqxmd.com/read/28226184/cd117-kit-is-a-useful-marker-in-the-diagnosis-of-plasmablastic-plasma-cell-myeloma
#17
Etan Marks, Yang Shi, Yanhua Wang
AIMS: Plasmablastic plasma cell myeloma (PPCM) is a rare morphological presentation of multiple myeloma and can resemble plasmablastic lymphoma (PBL), an HIV related lymphoid neoplasm, morphologically and immunophenotypically. We retrospectively searched for factors that could help differentiate these two entities. METHODS: We used Clinical Looking Glass (CLG), a data mining tool, to identify patients with a diagnosis of either PPCM or PBL with a CD117 test performed...
February 22, 2017: Histopathology
https://www.readbyqxmd.com/read/28213378/prognostic-role-of-circulating-exosomal-mirnas-in-multiple-myeloma
#18
Salomon Manier, Chia-Jen Liu, Hervé Avet-Loiseau, Jihye Park, Jiantao Shi, Federico Campigotto, Karma Z Salem, Daisy Huynh, Siobhan V Glavey, Bradley Rivotto, Antonio Sacco, Aldo M Roccaro, Juliette Bouyssou, Stéphane Minvielle, Philippe Moreau, Thierry Facon, Xavier Leleu, Edie Weller, Lorenzo Trippa, Irene M Ghobrial
Exosomes, secreted by several cell types, including cancer cells, can be isolated from the peripheral blood and have been shown to be powerful markers of disease progression in cancer. In this study, we examined the prognostic significance of circulating exosomal microRNAs (miRNAs) in multiple myeloma (MM). A cohort of 156 patients with newly diagnosed MM, uniformly treated and followed, was studied. Circulating exosomal miRNAs were isolated and used to perform a small RNA sequencing analysis on 10 samples and a quantitative reverse transcription polymerase chain reaction (qRT-PCR) array on 156 samples...
April 27, 2017: Blood
https://www.readbyqxmd.com/read/28151711/gene-expression-profiles-in-myeloma-ready-for-the-real-world
#19
EDITORIAL
Raphael Szalat, Herve Avet-Loiseau, Nikhil C Munshi
Multiple myeloma is a plasma cell malignancy characterized by molecular and clinical heterogeneity. The outcome of the disease has been dramatically improved with the advent of new drugs in the past few years. However, even in this context of increasing therapeutic options, important challenges remain, such as accurately evaluating patients' prognosis and predicting sensitivity to specific treatments and drug combinations. Transcriptomic studies have largely contributed to help decipher multiple myeloma complexity, characterizing multiple myeloma subgroups distinguished by different outcomes...
November 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28151579/mediator-cyclin-dependent-kinases-upregulate-transcription-of-inflammatory-genes-in-cooperation-with-nf-%C3%AE%C2%BAb-and-c-ebp%C3%AE-on-stimulation-of-toll-like-receptor-9
#20
Seiji Yamamoto, Tomoko Hagihara, Yoshiyuki Horiuchi, Akira Okui, Shotaro Wani, Tokuyuki Yoshida, Takao Inoue, Aki Tanaka, Takashi Ito, Yutaka Hirose, Yoshiaki Ohkuma
In eukaryotes, the Mediator complex has important roles in regulation of transcription by RNA polymerase II. Mediator is a large complex with more than 20 subunits that form head, middle, tail and CDK/cyclin modules. Among them, CDK8 and/or CDK19 (CDK8/19), and their counterpart cyclin C, form the CDK/cyclin module together with Mediator subunits MED12 and MED13. Despite evidences of both activation and repression, the precise functional roles of CDK8/19 in transcription are still elusive. Our previous results indicate that CDK8/19 recruits epigenetic regulators to repress immunoresponse genes...
March 2017: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
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