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https://www.readbyqxmd.com/read/28688466/leukemic-transformation-in-myeloproliferative-neoplasms-a-literature-review-on-risk-characteristics-and-outcome
#1
REVIEW
Meera Yogarajah, Ayalew Tefferi
Myeloproliferative neoplasms (MPNs) operationally include essential thrombocythemia, polycythemia vera, primary myelofibrosis (PMF), and prefibrotic PMF. All 4 MPN variants might progress into blast-phase disease (MPN-BP). For essential thrombocythemia, reported risk factors for leukemic transformation include advanced age, extreme thrombocytosis, anemia, leukocytosis, and sequence variants/mutations involving TP53 and EZH2 (for expansion of gene symbols, see www.genenames.org); for polycythemia vera, advanced age, leukocytosis, abnormal karyotype, mutations involving SRSF2 and IDH2, and treatment with pipobroman, chlorambucil, or P32; and for PMF, increased blast percentage, thrombocytopenia, abnormal karyotype, triple-negative driver mutational status, and sequence variants/mutations involving SRSF2, RUNX1, CEBPA, and SH2B3...
July 2017: Mayo Clinic Proceedings
https://www.readbyqxmd.com/read/28687222/tp53-and-idh2-somatic-mutations-are-associated-with-inferior-overall-survival-after-allogeneic-hematopoietic-cell-transplantation-for-myelodysplastic-syndrome
#2
Mohamed A Kharfan-Dabaja, Rami S Komrokji, Qing Zhang, Ambuj Kumar, Athanasios Tsalatsanis, Janelle Perkins, Taiga Nishihori, Teresa Field, Najla Al Ali, Asmita Mishra, David Sallman, Karma Z Salem, Ling Zhang, Lynn Moscinski, Hugo F Fernandez, Jeffrey Lancet, Alan List, Claudio Anasetti, Eric Padron
BACKGROUND: Next-generation sequencing has identified somatic mutations that are prognostic of cancer. PATIENTS AND METHODS: We evaluated the incidence and prognostic significance of somatic mutations in 89 myelodysplastic syndrome (MDS) patients who received an allogeneic hematopoietic cell transplantation. Next-generation sequencing was performed on paraffin embedded bone marrow, which was obtained at a median of 31 days before initiating the preparative regimen...
June 16, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28677265/epigenetics-in-myeloproliferative-neoplasms
#3
REVIEW
Suzanne McPherson, Mary Frances McMullin, Ken Mills
A decade on from the description of JAK2 V617F, the MPNs are circumscribed by an increasingly intricate landscape. There is now evidence that they are likely the result of combined genetic dysregulation, with several mutated genes involved in the regulation of epigenetic mechanisms. Epigenetic changes are not due to a change in the DNA sequence but are reversible modifications that dictate the way in which genes may be expressed (or silenced). Among the epigenetic mechanisms, DNA methylation is probably the best described...
July 4, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28675510/the-co-regulatory-networks-of-tumor-suppressor-genes-oncogenes-and-mirnas-in-colorectal-cancer
#4
Martha L Slattery, Jennifer S Herrick, Lila E Mullany, Wade S Samowitz, John R Sevens, Lori Sakoda, Roger K Wolff
Tumor suppressor genes (TSGs) and oncogenes (OG) are involved in carcinogenesis. MiRNAs also contribute to cellular pathways leading to cancer. We use data from 217 colorectal cancer (CRC) cases to evaluate differences in TSGs and OGs expression between paired CRC and normal mucosa and evaluate how TSGs and OGs are associated with miRNAs. Gene expression data from RNA-Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were used. We focus on genes most strongly associated with CRC (fold change (FC) of ≥1...
July 4, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28666271/the-distinct-clinical-features-of-giant-cell-tumor-of-bone-in-pagetic-and-non-pagetic-patients-are-associated-with-genetic-biochemical-and-histological-differences
#5
Giuseppina Divisato, Federica Scotto di Carlo, Laura Pazzaglia, Riccardo Rizzo, Domenico A Coviello, Maria Serena Benassi, Piero Picci, Teresa Esposito, Fernando Gianfrancesco
Giant Cell Tumor of Bone (GCT) is a tumor characterized by neoplastic mesenchymal stromal cells and a high number of osteoclast-like multinucleated giant cells. Rarely, GCT could arise in bones affected by Paget's disease of bone (GCT/PDB). Although it is already known that GCT/PDB and GCT show a different clinical profile regarding the age-onset and skeletal localization, our deep clinical comparison between the two GCT/PDB and GCT cohorts, permitted us to identify additional differences (e.g. focality, ALP serum levels, the 5-year survival rate and the familial recurrence), strongly suggesting a different molecular basis...
June 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28659444/positive-first-trial-of-enasidenib-for-aml
#6
(no author information available yet)
The first clinical trial of the investigational drug enasidenib, which targets IDH2 mutations, suggests that it is safe and may improve survival in patients with relapsed or refractory acute myeloid leukemia. It induced responses in 40.3% of patients, yielding a median overall survival of 9.3 months.
June 28, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28653623/replication-study-the-common-feature-of-leukemia-associated-idh1-and-idh2-mutations-is-a-neomorphic-enzyme-activity-converting-alpha-ketoglutarate-to-2-hydroxyglutarate
#7
Megan Reed Showalter, Jason Hatakeyama, Tomas Cajka, Kacey VanderVorst, Kermit L Carraway, Oliver Fiehn
In 2016, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Fiehn et al., 2016), that described how we intended to replicate selected experiments from the paper "The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate" (Ward et al., 2010). Here, we report the results of those experiments. We found that cells expressing R172K mutant IDH2 did not display isocitrate-dependent NADPH production above vector control levels, in contrast to the increased production observed with wild-type IDH2...
June 27, 2017: ELife
https://www.readbyqxmd.com/read/28653397/acute-myeloid-leukaemia-genomics
#8
REVIEW
Michael Medinger, Jakob R Passweg
Acute myeloid leukaemia (AML) is a biologically complex, molecularly and clinically heterogeneous disease. Despite major advances in understanding the genetic landscape of AML and its impact on the pathophysiology and biology of the disease, standard treatment options have not significantly changed during the past three decades. AML is characterized by multiple somatically acquired mutations that affect genes of different functional categories. Mutations in genes encoding epigenetic modifiers, such as DNMT3A, ASXL1, TET2, IDH1, and IDH2, are commonly acquired early and are present in the founding clone...
June 27, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28642005/expression-purification-and-crystallization-of-type-1-isocitrate-dehydrogenase-from-trypanosoma-brucei-brucei
#9
Xinying Wang, Daniel Ken Inaoka, Tomoo Shiba, Emmanuel Oluwadare Balogun, Stefan Allmann, Yoh-Ichi Watanabe, Michael Boshart, Kiyoshi Kita, Shigeharu Harada
Isocitrate dehydrogenases (IDHs) are metabolic enzymes that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate. Depending on the electron acceptor and subcellular localization, these enzymes are classified as NADP(+)-dependent IDH1 in the cytosol or peroxisomes, NADP(+)-dependent IDH2 and NAD(+)-dependent IDH3 in mitochondria. Trypanosoma brucei is a protozoan parasite that causes African sleeping sickness in humans and Nagana disease in animals. Here, for the first time, a putative glycosomal T...
June 20, 2017: Protein Expression and Purification
https://www.readbyqxmd.com/read/28638988/same-day-genomic-and-epigenomic-diagnosis-of-brain-tumors-using-real-time-nanopore-sequencing
#10
Philipp Euskirchen, Franck Bielle, Karim Labreche, Wigard P Kloosterman, Shai Rosenberg, Mailys Daniau, Charlotte Schmitt, Julien Masliah-Planchon, Franck Bourdeaut, Caroline Dehais, Yannick Marie, Jean-Yves Delattre, Ahmed Idbaih
Molecular classification of cancer has entered clinical routine to inform diagnosis, prognosis, and treatment decisions. At the same time, new tumor entities have been identified that cannot be defined histologically. For central nervous system tumors, the current World Health Organization classification explicitly demands molecular testing, e.g., for 1p/19q-codeletion or IDH mutations, to make an integrated histomolecular diagnosis. However, a plethora of sophisticated technologies is currently needed to assess different genomic and epigenomic alterations and turnaround times are in the range of weeks, which makes standardized and widespread implementation difficult and hinders timely decision making...
June 21, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28634614/detection-of-the-circulating-tumor-dnas-in-angioimmunoblastic-t-cell-lymphoma
#11
Mamiko Sakata-Yanagimoto, Rie Nakamoto-Matsubara, Daisuke Komori, Tran B Nguyen, Keiichiro Hattori, Toru Nanmoku, Takayasu Kato, Naoki Kurita, Yasuhisa Yokoyama, Naoshi Obara, Yuichi Hasegawa, Atsushi Shinagawa, Shigeru Chiba
Recent genetic studies identified that the disease-specific G17V RHOA mutation, together with mutations in TET2, DNMT3A, and IDH2, is a hallmark of angioimmunoblastic T cell lymphomas (AITL). The diagnostic value of these mutations is now being investigated. Circulating tumor DNAs (ctDNAs) may offer a non-invasive testing for diagnosis and disease monitoring of cancers. To investigate whether these mutations are useful markers for ctDNAs in AITL and its related lymphomas, we performed targeted sequencing for TET2, RHOA, DNMT3A, and IDH2 in paired tumors and cell-free DNAs from 14 patients at diagnosis...
June 20, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/28612220/individual-outcome-prediction-for-myelodysplastic-syndrome-mds-and-secondary-acute-myeloid-leukemia-from-mds-after-allogeneic-hematopoietic-cell-transplantation
#12
Michael Heuser, Razif Gabdoulline, Patrick Löffeld, Vera Dobbernack, Henriette Kreimeyer, Mira Pankratz, Madita Flintrop, Alessandro Liebich, Sabrina Klesse, Victoria Panagiota, Michael Stadler, Martin Wichmann, Rabia Shahswar, Uwe Platzbecker, Christian Thiede, Thomas Schroeder, Guido Kobbe, Robert Geffers, Brigitte Schlegelberger, Gudrun Göhring, Hans-Heinrich Kreipe, Ulrich Germing, Arnold Ganser, Nicolaus Kröger, Christian Koenecke, Felicitas Thol
We integrated molecular data with available prognostic factors in patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) for myelodysplastic syndrome (MDS) or secondary acute myeloid leukemia (sAML) from MDS to evaluate their impact on prognosis. Three hundred four patients were sequenced for mutations in 54 genes. We used a Cox multivariate model and competing risk analysis with internal and cross validation to identify factors prognostic of overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM)...
June 13, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/28601826/study-protocol-of-a-phase-ib-ii-clinical-trial-of-metformin-and-chloroquine-in-patients-with-idh1-mutated-or-idh2-mutated-solid-tumours
#13
Remco J Molenaar, Robert Js Coelen, Mohammed Khurshed, Eva Roos, Matthan Wa Caan, Myra E van Linde, Mathilde Kouwenhoven, Jos Am Bramer, Judith Vmg Bovée, Ron A Mathôt, Heinz-Josef Klümpen, Hanneke Wm van Laarhoven, Cornelis Jf van Noorden, W Peter Vandertop, Hans Gelderblom, Thomas M van Gulik, Johanna W Wilmink
INTRODUCTION: High-grade chondrosarcoma, high-grade glioma and intrahepatic cholangiocarcinoma are aggressive types of cancer with a dismal outcome. This is due to the lack of effective treatment options, emphasising the need for novel therapies. Mutations in the genes IDH1 and IDH2 (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. IDH1/2-mutated cancer cells produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are metabolically vulnerable to treatment with the oral antidiabetic metformin and the oral antimalarial drug chloroquine...
June 10, 2017: BMJ Open
https://www.readbyqxmd.com/read/28588020/enasidenib-in-mutant-idh2-relapsed-or-refractory-acute-myeloid-leukemia
#14
Eytan M Stein, Courtney D DiNardo, Daniel A Pollyea, Amir T Fathi, Gail J Roboz, Jessica K Altman, Richard M Stone, Daniel J DeAngelo, Ross L Levine, Ian W Flinn, Hagop M Kantarjian, Robert Collins, Manish R Patel, Arthur E Frankel, Anthony Stein, Mikkael A Sekeres, Ronan T Swords, Bruno C Medeiros, Christophe Willekens, Paresh Vyas, Alessandra Tosolini, Qiang Xu, Robert D Knight, Katharine E Yen, Sam Agresta, Stéphane de Botton, Martin S Tallman
Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ~12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, leading to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human, phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies...
June 6, 2017: Blood
https://www.readbyqxmd.com/read/28588019/enasidenib-induces-acute-myeloid-leukemia-cell-differentiation-to-promote-clinical-response
#15
Michael D Amatangelo, Lynn Quek, Alan Shih, Eytan M Stein, Mikhail Roshal, Muriel D David, Benoit Marteyn, Noushin Rahnamay Farnoud, Stephane de Botton, Olivier A Bernard, Bin Wu, Katharine E Yen, Martin S Tallman, Elli Papaemmanuil, Virginie Penard-Lacronique, Anjan Thakurta, Paresh Vyas, Ross L Levine
Recurrent mutations at R140 and R172 in isocitrate dehydrogenase 2 (IDH2) occur in many cancers, including ~12% of acute myeloid leukemia (AML). In preclinical models these mutations cause accumulation of the oncogenic metabolite R-2-hydroxyglutarate (2-HG) and induce hematopoietic differentiation block. Single-agent enasidenib (AG-221/CC-90007), a selective mutant IDH2 (mIDH2) inhibitor, produced an overall response rate of 40.3% in relapsed/refractory AML patients with mIDH2 in a phase 1 trial. However, its mechanism of action and biomarkers associated with response remain unclear...
June 6, 2017: Blood
https://www.readbyqxmd.com/read/28581676/comprehensive-genomic-profiling-of-different-subtypes-of-nasopharyngeal-carcinoma-reveals-similarities-and-differences-to-guide-targeted-therapy
#16
Siraj M Ali, Ming Yao, Jicheng Yao, Jing Wang, Yuwei Cheng, Alexa B Schrock, Gung-Wei Chirn, Hui Chen, Shuo Mu, Laurie Gay, Julia A Elvin, James Suh, Vincent A Miller, Philip J Stephens, Jeffrey S Ross, Kai Wang
BACKGROUND: To date, no targeted therapy has been approved for nasopharyngeal carcinoma (NPC), and this underscores the need for an in-depth understanding of clinically relevant genomic alterations (CRGAs). METHODS: Comprehensive genomic profiling was performed for 190 NPC patients, including 20 patients with nasopharyngeal adenocarcinoma (NPAC), 62 patients with nasopharyngeal squamous cell carcinoma (NPSCC), and 108 patients with nasopharyngeal undifferentiated carcinoma (NPUC)...
June 5, 2017: Cancer
https://www.readbyqxmd.com/read/28564604/cancer-associated-idh1-promotes-growth-and-resistance-to-targeted-therapies-in-the-absence-of-mutation
#17
Andrea E Calvert, Alexandra Chalastanis, Yongfei Wu, Lisa A Hurley, Fotini M Kouri, Yingtao Bi, Maureen Kachman, Jasmine L May, Elizabeth Bartom, Youjia Hua, Rama K Mishra, Gary E Schiltz, Oleksii Dubrovskyi, Andrew P Mazar, Marcus E Peter, Hongwu Zheng, C David James, Charles F Burant, Navdeep S Chandel, Ramana V Davuluri, Craig Horbinski, Alexander H Stegh
Oncogenic mutations in two isocitrate dehydrogenase (IDH)-encoding genes (IDH1 and IDH2) have been identified in acute myelogenous leukemia, low-grade glioma, and secondary glioblastoma (GBM). Our in silico and wet-bench analyses indicate that non-mutated IDH1 mRNA and protein are commonly overexpressed in primary GBMs. We show that genetic and pharmacologic inactivation of IDH1 decreases GBM cell growth, promotes a more differentiated tumor cell state, increases apoptosis in response to targeted therapies, and prolongs the survival of animal subjects bearing patient-derived xenografts (PDXs)...
May 30, 2017: Cell Reports
https://www.readbyqxmd.com/read/28554049/increased-susceptibility-of-idh2-deficient-mice-to-dextran-sodium-sulfate-induced-colitis
#18
Hanvit Cha, Seoyoon Lee, Sung Hwan Kim, Hyunjin Kim, Dong-Seok Lee, Hyun-Shik Lee, Jin Hyup Lee, Jeen-Woo Park
Inflammatory bowel disease (IBD) is a group of chronic, relapsing, immunological, inflammatory disorders of the gastrointestinal tract including ulcerative colitis (UC) and Crohn's disease (CD). It has been reported that UC, which is studied using a dextran sodium sulfate (DSS)-induced colitis model, is associated with the production of reactive oxygen species (ROS) and the apoptosis of intestine epithelial cells (IEC). Mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2) has been reported as an essential enzyme in the mitochondrial antioxidant system via generation of NADPH...
May 20, 2017: Redox Biology
https://www.readbyqxmd.com/read/28552826/diagnostic-utility-of-idh1-2-mutations-to-distinguish-dedifferentiated-chondrosarcoma-from-undifferentiated-pleomorphic-sarcoma-of-bone
#19
Shaoxiong Chen, Karen Fritchie, Shi Wei, Naser Ali, Kendra Curless, Tiansheng Shen, Anna T Brini, Farida Latif, Vaiyapuri Sumathi, Gene P Siegal, Liang Cheng
Histologically it is nearly impossible to distinguish the dedifferentiated component of dedifferentiated chondrosarcoma from undifferentiated pleomorphic sarcoma of bone when the low-grade cartilaginous component is absent. Previous studies have revealed that isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations are present in a significant number of cartilaginous tumors including the majority of conventional chondrosarcoma and dedifferentiated chondrosarcomas. These mutations have not been studied in undifferentiated pleomorphic sarcomas of bone...
May 25, 2017: Human Pathology
https://www.readbyqxmd.com/read/28549927/molecular-classification-of-adult-diffuse-gliomas-conflicting-idh1-idh2-atrx-and-1p-19q-results
#20
Leomar Y Ballester, Jason T Huse, Guilin Tang, Gregory N Fuller
Until recently, the diagnosis of brain tumors was primarily based on microscopic examination of hematoxylin and eosin (H&E) stained tissue sections. The updated World Health Organization (WHO) classification of tumours of the central nervous system (CNS) incorporates genetic alterations into the classification system, with the goal of creating more homogenous disease categories with greater prognostic value. Hence, under the new classification system the diagnosis of diffuse gliomas incorporates the evaluation of mutations in the IDH1 and IDH2 genes and simultaneous deletion of chromosomes 1p and 19...
May 23, 2017: Human Pathology
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