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B C Medeiros, A T Fathi, C D DiNardo, D A Pollyea, S M Chan, R Swords
Alterations to genes involved in cellular metabolism and epigenetic regulation are implicated in the pathogenesis of myeloid malignancies. Recurring mutations in isocitrate dehydrogenase (IDH) genes are detected in approximately 20% of adult patients with acute myeloid leukemia (AML) and 5% of adults with myelodysplastic syndromes (MDS). IDH proteins are homodimeric enzymes involved in diverse cellular processes, including adaptation to hypoxia, histone demethylation, and DNA modification. The IDH2 protein is localized in the mitochondria and is a critical component of the tricarboxylic acid (TCA, also called the 'citric acid' or Krebs) cycle...
October 10, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Chiara Bardella, Osama Al-Dalahmah, Daniel Krell, Pijus Brazauskas, Khalid Al-Qahtani, Marketa Tomkova, Julie Adam, Sébastien Serres, Helen Lockstone, Luke Freeman-Mills, Inga Pfeffer, Nicola Sibson, Robert Goldin, Benjamin Schuster-Böeckler, Patrick J Pollard, Tomoyoshi Soga, James S McCullagh, Christopher J Schofield, Paul Mulholland, Olaf Ansorge, Skirmantas Kriaucionis, Peter J Ratcliffe, Francis G Szele, Ian Tomlinson
Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1(R132H) in the subventricular zone (SVZ) of the adult mouse brain. The mice developed hydrocephalus and grossly dilated lateral ventricles, with accumulation of 2-hydroxyglutarate and reduced α-ketoglutarate. Stem and transit amplifying/progenitor cell populations were expanded, and proliferation increased. Cells expressing SVZ markers infiltrated surrounding brain regions...
October 10, 2016: Cancer Cell
Tibor Szénási, Judit Oláh, Adél Szabó, Sándor Szunyogh, András Láng, András Perczel, Attila Lehotzky, Vladimir N Uversky, Judit Ovádi
The hallmarks of Parkinson's disease and other synucleinopathies, Tubulin Polymerization Promoting Protein (TPPP/p25) and α-synuclein (SYN) have two key features: they are disordered and co-enriched/co-localized in brain inclusions. These Neomorphic Moonlighting Proteins display both physiological and pathological functions due to their interactions with distinct partners. To achieve the selective targeting of the pathological TPPP/p25-SYN but not the physiological TPPP/p25-tubulin complex, their interfaces were identified as a specific innovative strategy for the development of anti-Parkinson drugs...
September 23, 2016: Biochimica et Biophysica Acta
Gaurav Verma, Suyash Mohan, MacLean P Nasrallah, Steven Brem, John Y K Lee, Sanjeev Chawla, Sumei Wang, Rajakumar Nagarajan, M Albert Thomas, Harish Poptani
BACKGROUND: Mutations in the isocitrate dehydrogenase enzyme are present in a majority of lower-grade gliomas and secondary glioblastomas. This mis-sense mutation results in the neomorphic reduction of isocitrate dehydrogenase resulting in an accumulation of the "oncometabolite" 2-hydroxyglutarate (2HG). Detection of 2HG can thus serve as a surrogate biomarker for these mutations, with significant translational implications including improved prognostication. Two dimensional localized correlated spectroscopy (2D L-COSY) at 7T is a highly-sensitive non-invasive technique for assessing brain metabolism...
2016: Journal of Translational Medicine
(no author information available yet)
Gordon Mills, MD, PhD, chair of systems biology at The University of Texas MD Anderson Cancer Center in Houston, discusses a third category of genomic aberrations besides oncogene activation or tumor suppressor inactivation: neomorphs, or mutations that rewire cellular signaling in unexpected ways, with important functional consequences.
October 2016: Cancer Discovery
Xing Chen, Hongmei Wang, Weibing Yu, Fen Chen, Guiyun Wang, Jiajia Shi, Chunying Zhou
Isocitrate dehydrogenase 1 (IDH1), one member of the IDH family can convert isocitrate to α-ketoglutarate (α-KG) via oxidative decarboxylation. IDH1 and IDH2 mutations have been identified in multiple tumor types and the mutations confer neomorphic activity in the mutant protein, resulting in the conversion of α-KG to the oncometabolite, D-2-hydroxyglutarate (2-HG). The subsequent accumulation of 2-HG results in epigenetic dysregulation via inhibition of α-KG-dependent histone and DNA demethylase. And the glutamate levels are reduced in IDH mutant cells compared to wild-type...
August 27, 2016: Cellular and Molecular Neurobiology
Ping Song, Shan Li, Yatao Wu, Changqi Lv, Peng Wang, Guoping Zhu
Arginine 132 (R132) mutations to histidine or cysteine frequently occur to cytosolic NADP(+) -isocitrate dehydrogenase (IDH1) in secondary glioblastoma multiforme (GBM) patients, in which GBM develops from a lower grade astroctyoma. Mutant enzymes lose the normal IDH activity, but acquire a neomorphic ability of producing 2-hydroxyglutarate (2-HG) from α-ketoglutarate (α-KG). In the present study, the analogous mutations, Arg to His or Cys, were employed to homologous Arg153 of the NADP(+) -IDH from Escherichia coli (EcIDH), generating two mutants: EcIDH R153 H and EcIDH R153C...
July 13, 2016: Journal of Basic Microbiology
Yanzhe Gao, Elizabeth Mutter-Rottmayer, Alicia M Greenwalt, Dennis Goldfarb, Feng Yan, Yang Yang, Raquel C Martinez-Chacin, Kenneth H Pearce, Satoshi Tateishi, Michael B Major, Cyrus Vaziri
Trans-lesion synthesis (TLS) is an important DNA-damage tolerance mechanism that permits ongoing DNA synthesis in cells harbouring damaged genomes. The E3 ubiquitin ligase RAD18 activates TLS by promoting recruitment of Y-family DNA polymerases to sites of DNA-damage-induced replication fork stalling. Here we identify the cancer/testes antigen melanoma antigen-A4 (MAGE-A4) as a tumour cell-specific RAD18-binding partner and an activator of TLS. MAGE-A4 depletion from MAGE-A4-expressing cancer cells destabilizes RAD18...
2016: Nature Communications
Takeo Fujii, Muhammad Rizwan Khawaja, Courtney D DiNardo, Johnique T Atkins, Filip Janku
Isocitrate dehydrogenase (IDH) is an essential enzyme for cellular respiration in the tricarboxylic acid (TCA) cycle. Recurrent mutations in IDH1 or IDH2 are prevalent in several cancers including glioma, acute myeloid leukemia (AML), cholangiocarcinoma and chondrosarcoma. The mutated IDH1 and IDH2 proteins have a gain-of-function, neomorphic activity, catalyzing the reduction of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG) by NADPH. Cancer-associated IDH mutations block normal cellular differentiation and promote tumorigenesis via the abnormal production of the oncometabolite 2-HG...
May 2016: Discovery Medicine
Stéphane J H Ricoult, Christian C Dibble, John M Asara, Brendan D Manning
Sterol regulatory element binding protein (SREBP) is a major transcriptional regulator of the enzymes underlying de novo lipid synthesis. However, little is known about the SREBP-mediated control of processes that indirectly support lipogenesis, for instance, by supplying reducing power in the form of NAPDH or directing carbon flux into lipid precursors. Here, we characterize isocitrate dehydrogenase 1 (IDH1) as a transcriptional target of SREBP across a spectrum of cancer cell lines and human cancers. IDH1 promotes the synthesis of lipids specifically from glutamine-derived carbons...
September 15, 2016: Molecular and Cellular Biology
Beth G Gibson, Michael D Briggs
The large chondroitin sulphated proteoglycan aggrecan (ACAN) is the most abundant non-collagenous protein in cartilage and is essential for its structure and function. Mutations in ACAN result in a broad phenotypic spectrum of non-lethal skeletal dysplasias including spondyloepimetaphyseal dysplasia, spondyloepiphyseal dysplasia, familial osteochondritis dissecans and various undefined short stature syndromes associated with accelerated bone maturation. However, very little is currently known about the disease pathways that underlie these aggrecanopathies, although they are likely to be a combination of haploinsufficiency and dominant-negative (neomorphic) mechanisms...
2016: Orphanet Journal of Rare Diseases
Lydia Wt Cheung, Gordon B Mills
PIK3R1 (encoding the p85α subunit of phosphatidylinositol 3-kinase) is the 11th most frequently mutated gene across tumors. We recently reported neomorphic p85α mutants that induce signaling cascades not predicted by the canonical functions of p85α, suggesting the need to functionally annotate specific mutations in cancer genes for effective genome-informed personalized therapy.
October 2015: Molecular & Cellular Oncology
Jiao Chen, Jie Yang, Peng Cao
Isocitrate dehydrogenase (IDH) is a metabolic enzyme that converts isocitrate to α-ketoglutarate (α-KG). Genetic gain-of-function mutations in IDH1 and IDH2 confers a neomorphic activity that allows reduction of α-KG to (R)-2-hydroxyglutarate, the accumulation of which results in the development of cancers like low grade gliomas and leukemia. After treatment with AG-221 in clinical trials, a first-in-class inhibitor of mutated IDH2, 29 patients with acute myeloid leukemia or myelodysplastic syndrome experience complete remissions and the overall response rate is 59/159 (37%)...
June 8, 2016: Mini Reviews in Medicinal Chemistry
Takumi Ito, Hideki Ando, Hiroshi Handa
Half a century ago, the sedative thalidomide caused a serious drug disaster because of its teratogenicity and was withdrawn from the market. However, thalidomide, which has returned to the market, is now used for the treatment of leprosy and multiple myeloma (MM) under strict control. The mechanism of thalidomide action had been a long-standing question. We developed a new affinity bead technology and identified cereblon (CRBN) as a thalidomide-binding protein. We found that CRBN functions as a substrate receptor of an E3 cullin-Ring ligase complex 4 (CRL4) and is a primary target of thalidomide teratogenicity...
May 2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Satish K Chitneni, Zachary J Reitman, David M Gooden, Hai Yan, Michael R Zalutsky
INTRODUCTION: Malignant gliomas frequently harbor mutations in the isocitrate dehydrogenase 1 (IDH1) gene. Studies suggest that IDH mutation contributes to tumor pathogenesis through mechanisms that are mediated by the neomorphic metabolite of the mutant IDH1 enzyme, 2-hydroxyglutarate (2-HG). The aim of this work was to synthesize and evaluate radiolabeled compounds that bind to the mutant IDH1 enzyme with the goal of enabling noninvasive imaging of mutant IDH1 expression in gliomas by positron emission tomography (PET)...
August 25, 2016: European Journal of Medicinal Chemistry
Kamila Rosiak, Maciej Smolarz, Wojciech J Stec, Joanna Peciak, Dawid Grzela, Marta Winiecka-Klimek, Ewelina Stoczynska-Fidelus, Barbara Krynska, Sylwester Piaskowski, Piotr Rieske
BACKGROUND: The high frequency of mutations in the isocitrate dehydrogenase 1 (IDH1) gene in diffuse gliomas indicates its importance in the process of gliomagenesis. These mutations result in loss of the normal function and acquisition of the neomorphic activity converting α-ketoglutarate to 2-hydroxyglutarate. This potential oncometabolite may induce the epigenetic changes, resulting in the deregulated expression of numerous genes, including those related to the differentiation process or cell survivability...
2016: PloS One
Pavithra Viswanath, Myriam M Chaumeil, Sabrina M Ronen
Mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) have recently been identified as drivers in the development of several tumor types. Most notably, cytosolic IDH1 is mutated in 70-90% of low-grade gliomas and upgraded glioblastomas, and mitochondrial IDH2 is mutated in ~20% of acute myeloid leukemia cases. Wild-type IDH catalyzes the interconversion of isocitrate to α-ketoglutarate (α-KG). Mutations in the enzyme lead to loss of wild-type enzymatic activity and a neomorphic activity that converts α-KG to 2-hydroxyglutarate (2-HG)...
2016: Frontiers in Oncology
L Dang, K Yen, E C Attar
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes, converting isocitrate to α-ketoglutarate (αKG).IDH1 and IDH2 mutations have been identified in multiple tumor types, including gliomas and myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Here we provide an overview of the function of normal and mutated IDH, discuss the role of IDH mutations in tumorigenesis and progression and review the key clinical considerations when treating IDH-mutated tumors based on emerging clinical data from mutant IDH1/2 inhibitor trials...
April 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Daniel J Hodson, Arthur L Shaffer, Wenming Xiao, George W Wright, Roland Schmitz, James D Phelan, Yandan Yang, Daniel E Webster, Lixin Rui, Holger Kohlhammer, Masao Nakagawa, Thomas A Waldmann, Louis M Staudt
The requirement for the B-cell transcription factor OCT2 (octamer-binding protein 2, encoded by Pou2f2) in germinal center B cells has proved controversial. Here, we report that germinal center B cells are formed normally after depletion of OCT2 in a conditional knockout mouse, but their proliferation is reduced and in vivo differentiation to antibody-secreting plasma cells is blocked. This finding led us to examine the role of OCT2 in germinal center-derived lymphomas. shRNA knockdown showed that almost all diffuse large B-cell lymphoma (DLBCL) cell lines are addicted to the expression of OCT2 and its coactivator OCA-B...
April 5, 2016: Proceedings of the National Academy of Sciences of the United States of America
Koichi Ichimura, Shintaro Fukushima, Yasushi Totoki, Yuko Matsushita, Ayaka Otsuka, Arata Tomiyama, Tohru Niwa, Hirokazu Takami, Taishi Nakamura, Tomonari Suzuki, Kohei Fukuoka, Takaaki Yanagisawa, Kazuhiko Mishima, Yoichi Nakazato, Fumie Hosoda, Yoshitaka Narita, Soichiro Shibui, Akihiko Yoshida, Akitake Mukasa, Nobuhito Saito, Toshihiro Kumabe, Masayuki Kanamori, Teiji Tominaga, Keiichi Kobayashi, Saki Shimizu, Motoo Nagane, Toshihiko Iuchi, Masahiro Mizoguchi, Koji Yoshimoto, Kaoru Tamura, Taketoshi Maehara, Kazuhiko Sugiyama, Mitsutoshi Nakada, Keiichi Sakai, Yonehiro Kanemura, Masahiro Nonaka, Akio Asai, Kiyotaka Yokogami, Hideo Takeshima, Nobutaka Kawahara, Tatsuya Takayama, Masahiro Yao, Mamoru Kato, Hiromi Nakamura, Natsuko Hama, Ryuichi Sakai, Toshikazu Ushijima, Masao Matsutani, Tatsuhiro Shibata, Ryo Nishikawa
Germ cell tumors constitute a heterogeneous group that displays a broad spectrum of morphology. They often arise in testes; however, extragonadal occurrence, in particular brain, is not uncommon, and whether they share a common pathogenesis is unknown. We performed whole exome sequencing in 41 pairs of central nervous system germ cell tumors (CNS GCTs) of various histology and their matched normal tissues. We then performed targeted sequencing of 41 selected genes in a total of 124 CNS GCTs, 65 testicular germ cell tumors (tGCTs) and 8 metastatic GCTs to the CNS...
June 2016: Acta Neuropathologica
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