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Sergio Pina-Oviedo, Carlos A Torres-Cabala, Roberto N Miranda, Michael T Tetzlaff, Selina Singh, Ronald P Rapini, Victor G Prieto, Phyu P Aung
Leukemia cutis develops in <4% of all acute leukemias. Concurrent acute myeloid leukemia (AML) and Langerhans cell histiocytosis (LCH) is rare, with most cases involving lymph nodes or spleen, and no cutaneous involvement. We report the case of a 59-year-old man who presented with fever, malaise, and fatigue. The CBC showed leukocytosis (30.4 × 10/L, 9% blasts), anemia, and thrombocytopenia. Bone marrow biopsy was diagnosed with AML, not otherwise specified, with mutations of FLT3 and IDH2 (R140Q). The patient developed skin rash on the right flank with the clinical differential diagnosis of herpes simplex virus or varicella-zoster virus infection/reactivation versus leukemia cutis...
October 18, 2016: American Journal of Dermatopathology
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
Brigitta G Baumert, Monika E Hegi, Martin J van den Bent, Andreas von Deimling, Thierry Gorlia, Khê Hoang-Xuan, Alba A Brandes, Guy Kantor, Martin J B Taphoorn, Mohamed Ben Hassel, Christian Hartmann, Gail Ryan, David Capper, Johan M Kros, Sebastian Kurscheid, Wolfgang Wick, Roelien Enting, Michele Reni, Brian Thiessen, Frederic Dhermain, Jacoline E Bromberg, Loic Feuvret, Jaap C Reijneveld, Olivier Chinot, Johanna M M Gijtenbeek, John P Rossiter, Nicolas Dif, Carmen Balana, Jose Bravo-Marques, Paul M Clement, Christine Marosi, Tzahala Tzuk-Shina, Robert A Nordal, Jeremy Rees, Denis Lacombe, Warren P Mason, Roger Stupp
BACKGROUND: Outcome of low-grade glioma (WHO grade II) is highly variable, reflecting molecular heterogeneity of the disease. We compared two different, single-modality treatment strategies of standard radiotherapy versus primary temozolomide chemotherapy in patients with low-grade glioma, and assessed progression-free survival outcomes and identified predictive molecular factors. METHODS: For this randomised, open-label, phase 3 intergroup study (EORTC 22033-26033), undertaken in 78 clinical centres in 19 countries, we included patients aged 18 years or older who had a low-grade (WHO grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) with at least one high-risk feature (aged >40 years, progressive disease, tumour size >5 cm, tumour crossing the midline, or neurological symptoms), and without known HIV infection, chronic hepatitis B or C virus infection, or any condition that could interfere with oral drug administration...
September 26, 2016: Lancet Oncology
Jiangjiang Li, Jingchen Lu, Ya He, Yong Wu, Yuan Wu, Xin Song, Yuee Jiang, Min Tang, Xinxian Weng, Wei Yi, Xiangjian Luo, Lunquan Sun, Ann M Bode, Ya Cao
Recently, mutations in isocitrate dehydrogenase 1/2 (IDH1/2) were discovered in 70% of low-grade glioma and secondary glioblastoma multiforme. The discovery of an oncogenic function and the identification of onco-metabolites of IDH1/2 support new roles for metabolism in cancer. For example, some evidence indicates that IDH2 might also exhibit oncogenic functions by promoting cellular metabolism and cancer cell growth. We examined the association between IDH2 rs11540478 and lung cancer risk in 262 lung cancer patient cases and 602 healthy control subjects and also investigated the biological function of rs11540478 in vivo...
September 20, 2016: Molecular Carcinogenesis
Johanna Mondesir, Christophe Willekens, Mehdi Touat, Stéphane de Botton
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that convert isocitrate to α-ketoglutarate. IDH1/2 mutations define distinct subsets of cancers, including low-grade gliomas and secondary glioblastomas, chondrosarcomas, intrahepatic cholangiocarcinomas, and hematologic malignancies. Somatic point mutations in IDH1/2 confer a gain-of-function in cancer cells, resulting in the accumulation and secretion in vast excess of an oncometabolite, the D-2-hydroxyglutarate (D-2HG). Overproduction of D-2HG interferes with cellular metabolism and epigenetic regulation, contributing to oncogenesis...
2016: Journal of Blood Medicine
Akimasa Hayashi, Kento Misumi, Junji Shibahara, Norihiro Kokudo, Yukinari Kato, Masashi Fukayama
Immunohistochemical analysis using specific antibodies is a useful and convenient method to detect proteins altered by somatic mutations. We previously generated the rat monoclonal antibody MsMab-2, which recognizes isocitrate dehydrogenase (IDH)1 R132L and IDH2 R172M. In the present study, we used an immunohistochemical method to examine MsMab-2 immunoreactivity in 95 cases of intrahepatic cholangiocarcinoma, including five IDH1 R132L and one IDH2 R172M mutant cases confirmed by direct sequencing. Tissue microarray section slides of all IDH1/2-mutant and wild-type cases, as well as whole section slides of IDH1 R132L and IDH2 R172M cases were immunostained using an autostainer...
October 2016: Pathology International
Walid-Sabri Hamadou, Violaine Bourdon, Sébastien Létard, Fabienne Brenet, Sofien Laarif, Sawsen Besbes, Angelo Paci, Muriel David, Virginie Penard-Lacronique, Yosra Ben Youssef, Mohamed-Adnène Laatiri, François Eisinger, Véronique Mari, Paul Gesta, Hélène Dreyfus, Valérie Bonadona, Catherine Dugast, Hélène Zattara, Laurence Faivre, Testsuro Noguchi, Abderrahim Khélif, Chaker Ben Salem, Patrice Dubreuil, Hagay Sobol, Zohra Soua
Isocitrate dehydrogenase IDH 1 and IDH 2 mutations were reported in several cancer forms, especially in hematological malignancies, but were never been investigated in familial aggregation. The aim of this study is to determine whether germline isocitrate dehydrogenase genes mutations are involved.We targeted IDH1 and IDH2 genes in 104 familial cases belonging to Tunisian and French populations, including several forms of hematological malignancies and cosegregated solid tumors.We report one IDH1 variant: c...
September 3, 2016: Annals of Hematology
Anja Karlstaedt, Xiaotian Zhang, Heidi Vitrac, Romain Harmancey, Hernan Vasquez, Jing Han Wang, Margaret A Goodell, Heinrich Taegtmeyer
Hematologic malignancies are frequently associated with cardiac pathologies. Mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in a subset of acute myeloid leukemia patients, causing metabolic and epigenetic derangements. We have now discovered that altered metabolism in leukemic cells has a profound effect on cardiac metabolism. Combining mathematical modeling and in vivo as well as ex vivo studies, we found that increased amounts of the oncometabolite d-2-hydroxyglutarate (D2-HG), produced by IDH2 mutant leukemic cells, cause contractile dysfunction in the heart...
September 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
Jing-Yi Chen, You-Syuan Lai, Hui-Jen Tsai, Cheng-Chin Kuo, B Linju Yen, Su-Peng Yeh, H Sunny Sun, Wen-Chun Hung
Mutations of isocitrate dehydrogenase 1 (IDH1) and IDH2 in acute myeloid leukemia (AML) cells produce the oncometabolite R-2-hydroxyglutarate (R-2HG) to induce epigenetic alteration and block hematopoietic differentiation. However, the effect of R-2HG released by IDH-mutated AML cells on the bone marrow microenvironment is unclear. Here, we report that R-2HG induces IκB kinase-independent activation of NF-κB in bone marrow stromal cells. R-2HG acts via a reactive oxygen species/extracellular signal-regulated kinase (ERK)-dependent pathway to phosphorylate NF-κB on the Thr254 residue...
2016: Scientific Reports
Emna Abdelhamid, Sawsen Besbes, Aline Renneville, Olivier Nibourel, Nathalie Helevaut, Claude Preudhomme, Zohra Soua
BACKGROUND: With the growing importance of minimal residual disease (MRD) monitoring and the recent discover of IDH mutations in acute myeloid leukemia (AML), the quantification of this molecular marker provides the possibility to monitor the disease progression and the therapy efficacy. OBJECTIVE: The aim of this study is to assess the MRD in AML for the first time with IDH1 and IDH2 gene mutations in 15 AML patients. METHODS: We have screened R132 IDH1, R140 IDH2 and R172 IDH2 mutations by PCR amplification and direct sequencing and we have quantified them for the first time by RQ-PCR using reverse primers modified by an LNA...
March 2016: La Tunisie Médicale
Justin M Watts, Bogdan Dumitriu, Patrick Hilden, Ashwin Kishtagari, Franck Rapaport, Christina Chen, Jihae Ahn, Sean M Devlin, Eytan M Stein, Raajit Rampal, Ross L Levine, Neal Young, Martin S Tallman
We examined the genetic implications and clinical impact of telomere length (TL) in 67 patients with acute myeloid leukemia (AML). There was a trend toward improved survival at 6 months in patients with longer TL. We found that patients with activating mutations, such as FLT3-ITD, had shorter TL, while those with mutations in epigenetic modifying enzymes, particularly IDH1 and IDH2, had longer TL. These are intriguing findings that warrant further investigation in larger cohorts. Our data show the potential of TL as a predictive biomarker in AML and identify genetic subsets that may be particularly vulnerable to telomere-targeted therapies...
October 2016: Leukemia Research
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
Yu Kitago, Mika K Kaneko, Satoshi Ogasawara, Yukinari Kato, Junichi Takagi
A point mutation in isocitrate dehydrogenase 1 (IDH1) and IDH2 is directly linked to the pathogenesis of certain types of tumors. To detect this mutation, several antibodies that can distinguish between mutant and wild-type enzymes have been established. One of which, MsMab-1, has a unique multi-specific character against several types of mutated IDH1/2. This promiscuous character is in remarkable contrast to the highly specific antigen recognition typically observed with a monoclonal antibody. We solved the crystal structure of MsMab-1 Fab fragment in complex with either IDH1 or IDH2-derived peptides...
September 23, 2016: Biochemical and Biophysical Research Communications
Jung-Hyun Kim, Deepali N Shinde, Margot R F Reijnders, Natalie S Hauser, Rebecca L Belmonte, Gregory R Wilson, Daniëlle G M Bosch, Paula A Bubulya, Vandana Shashi, Slavé Petrovski, Joshua K Stone, Eun Young Park, Joris A Veltman, Margje Sinnema, Connie T R M Stumpel, Jos M Draaisma, Joost Nicolai, Helger G Yntema, Kristin Lindstrom, Bert B A de Vries, Tamison Jewett, Stephanie L Santoro, Julie Vogt, Kristine K Bachman, Andrea H Seeley, Alyson Krokosky, Clesson Turner, Luis Rohena, Maja Hempel, Fanny Kortüm, Davor Lessel, Axel Neu, Tim M Strom, Dagmar Wieczorek, Nuria Bramswig, Franco A Laccone, Jana Behunova, Helga Rehder, Christopher T Gordon, Marlène Rio, Serge Romana, Sha Tang, Dima El-Khechen, Megan T Cho, Kirsty McWalter, Ganka Douglas, Berivan Baskin, Amber Begtrup, Tara Funari, Kelly Schoch, Alexander P A Stegmann, Servi J C Stevens, Dong-Er Zhang, David Traver, Xu Yao, Daniel G MacArthur, Han G Brunner, Grazia M Mancini, Richard M Myers, Laurie B Owen, Ssang-Taek Lim, David L Stachura, Lisenka E L M Vissers, Eun-Young Erin Ahn
The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations...
September 1, 2016: American Journal of Human Genetics
Su Jeong Lee, Sung Hwan Kim, Kwon Moo Park, Jin Hyup Lee, Jeen-Woo Park
Reactive oxygen species (ROS) are a byproduct of normal metabolism and play important roles in cell signaling and homeostasis. Mitochondria, the main organelles involved in intracellular ROS production, play central roles in modulating redox-dependent cellular processes such as metabolism and apoptosis. We recently reported an important role for mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2) in cellular redox regulation. Here, we show that mice with targeted disruption of IDH2 exhibit resistance to obesity, with lower body weight and reduced visceral fat, and increased insulin sensitivity accompanied by enhanced energy expenditure relative to controls...
August 9, 2016: Free Radical Biology & Medicine
M Kontro, A Kumar, M M Majumder, S Eldfors, A Parsons, T Pemovska, J Saarela, B Yadav, D Malani, Y Fløisand, M Höglund, K Remes, B T Gjertsen, O Kallioniemi, K Wennerberg, C A Heckman, K Porkka
Inhibitors of BCL-2 such as venetoclax (ABT-199) and navitoclax (ABT-263) are clinically explored in several cancer types, including acute myeloid leukemia (AML), to selectively induce apoptosis in cancer cells. To identify robust biomarkers for BCL-2 inhibitor sensitivity, we evaluated the ex vivo sensitivity of fresh leukemic cells from 73 diagnosed and relapsed/refractory AML patients, then comprehensively assessed if the responses correlated to specific mutations or gene expression signatures. Compared to samples from healthy donor controls (non-sensitive) and chronic lymphocytic leukemia (CLL) patients (highly-sensitive), AML samples exhibited variable responses to BCL-2 inhibition...
August 8, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Manuel Buscarlet, Alain Tessier, Sylvie Provost, Luigina Mollica, Lambert Busque
Epigenetic alteration may play a role in age-associated dysfunction of stem cells, and predispose to the development of hematological cancers. We analysed global levels of hematopoietic 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) in a cross sectional study comprising 198 unrelated individuals from four age categories (neonates, 25-30, 70-75, and >90 years old) by mass spectrometry (LC-ESI-MS/MS-MRM). X-chromosome inactivation (XCI) ratios and telomere length (TL) were measured in all individuals by PCR...
July 27, 2016: Experimental Hematology
Fang Wang, Jeremy Travins, Zhizhong Lin, Yaguang Si, Yue Chen, Josh Powe, Stuart Murray, Dongwei Zhu, Erin Artin, Stefan Gross, Stephanie Santiago, Mya Steadman, Andrew Kernytsky, Kimberly Straley, Chenming Lu, Ana Pop, Eduard A Struys, Erwin E W Jansen, Gajja S Salomons, Muriel D David, Cyril Quivoron, Virginie Penard-Lacronique, Karen S Regan, Wei Liu, Lenny Dang, Hua Yang, Lee Silverman, Samuel Agresta, Marion Dorsch, Scott Biller, Katharine Yen, Yong Cang, Shin-San Michael Su, Shengfang Jin
D-2-hydroxyglutaric aciduria (D2HGA) type II is a rare neurometabolic disorder caused by germline gain-of-function mutations in isocitrate dehydrogenase 2 (IDH2), resulting in accumulation of D-2-hydroxyglutarate (D2HG). Patients exhibit a wide spectrum of symptoms including cardiomyopathy, epilepsy, developmental delay and limited life span. Currently, there are no effective therapeutic interventions. We generated a D2HGA type II mouse model by introducing the Idh2R140Q mutation at the native chromosomal locus...
November 2016: Journal of Inherited Metabolic Disease
Nan-Hua Chou, Chung-Yu Tsai, Ya-Ting Tu, Kuo-Chiang Wang, Chi-Hsiang Kang, Po-Min Chang, Guan-Cheng Li, Hing-Chung Lam, Shiuh-Inn Liu, Kuo-Wang Tsai
The isocitrate dehydrogenase (IDH) family of enzymes comprises of the key functional metabolic enzymes in the Krebs cycle that catalyze the conversion of isocitrate to α-ketoglutarate (α-KG). α-KG acts as a cofactor in the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). However, the relationship between 5hmC and IDH in gastric cancer remains unclear. Our study revealed that the 5hmC level was substantially lower and 5mC level was slightly higher in gastric cancer tissues; however, 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) levels did not change significantly in these tissues...
August 2016: Anticancer Research
Masaya Miyazaki, Keita Yashiro, Mishie Tanino, Shinya Tanaka, Yasunori Fujioka
Chondromas are benign tumors that can be found at several sites in the body, while those arising from the dura mater are extremely rare. Among them, although chondromas arising from the cranial dura mater have been reported, those arising from the spinal dura mater have not been reported in the literature to date. A 66-year-old woman presented with right-sided continuous backache which she had developed recently. After detailed examinations, an epidural tumor at the thoracic level was detected. The patient underwent surgery and a total en-bloc resection was accomplished...
September 2016: Pathology, Research and Practice
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