keyword
MENU ▼
Read by QxMD icon Read
search

Neomorph

keyword
https://www.readbyqxmd.com/read/28705010/isocitrate-dehydrogenase-mutation-as-a-therapeutic-target-in-gliomas
#1
Catherine H Han, Tracy T Batchelor
Isocitrate dehydrogenases (IDH) are important enzymes that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), producing NADPH in the process. More than 80% of low-grade gliomas and secondary glioblastoma (GBM) harbor an IDH mutation. IDH mutations involve the catalytic pocket of the enzyme and lead to a neomorphic ability to produce 2-hydroxyglutarate (2HG) while oxidizing NADPH to NADP+. 2HG is considered as an 'oncometabolite' which is thought to be responsible for many, if not all, biologic effects of IDH mutations...
June 2017: Chinese Clinical Oncology
https://www.readbyqxmd.com/read/28663574/vitamin-c-induced-epigenomic-remodelling-in-idh1-mutant-acute-myeloid-leukaemia
#2
M Mingay, A Chaturvedi, M Bilenky, Q Cao, L Jackson, T Hui, M Moksa, A Heravi-Moussavi, R K Humphries, M Heuser, M Hirst
The genomes of myeloid malignancies are characterized by epigenomic abnormalities. Heterozygous, inactivating ten-eleven translocation 2 (TET2) mutations and neomorphic isocitrate dehydrogenase (IDH) mutations are recurrent and mutually exclusive in acute myeloid leukaemia genomes. Ascorbic acid (vitamin C) has been shown to stimulate the catalytic activity of TET2 in vitro and thus we sought to explore its effect in a leukaemic model expressing IDH1(R132H). Vitamin C treatment induced an IDH1(R132H)-dependent reduction in cell proliferation and an increase in expression of genes involved in leukocyte differentiation...
June 2, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28662348/abnormal-wnt5a-signaling-causes-mandibular-hypoplasia-in-robinow-syndrome
#3
S Hosseini-Farahabadi, S J Gignac, A Danescu, K Fu, J M Richman
The study of rare genetic diseases provides valuable insights into human gene function. Here, we investigate dominant Robinow syndrome (RS), which affects the WNT5A signaling pathway. Autosomal dominant RS is caused by missense mutations in WNT5A or nonsense mutations in the adaptor protein DVL1 or DVL3. The recessive form of the disease is caused by loss-of-function mutations in the receptor ROR2. RS is characterized by hypertelorism, midface, and mandibular hypoplasia. Here, we focus on the missense mutations in WNT5A, since the impact on function is difficult to predict from in silico analysis...
June 1, 2017: Journal of Dental Research
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
#4
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/28588020/enasidenib-in-mutant-idh2-relapsed-or-refractory-acute-myeloid-leukemia
#5
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, Stephane 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, which leads 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...
August 10, 2017: Blood
https://www.readbyqxmd.com/read/28467784/in-silico-gene-expression-analysis-reveals-glycolysis-and-acetate-anaplerosis-in-idh1-wild-type-glioma-and-lactate-and-glutamate-anaplerosis-in-idh1-mutated-glioma
#6
Mohammed Khurshed, Remco J Molenaar, Krissie Lenting, William P Leenders, Cornelis J F van Noorden
Hotspot mutations in isocitrate dehydrogenase 1 (IDH1) initiate low-grade glioma and secondary glioblastoma and induce a neomorphic activity that converts α-ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (D-2-HG). It causes metabolic rewiring that is not fully understood. We investigated the effects of IDH1 mutations (IDH1MUT) on expression of genes that encode for metabolic enzymes by data mining The Cancer Genome Atlas. We analyzed 112 IDH1 wild-type (IDH1WT) versus 399 IDH1MUT low-grade glioma and 157 IDH1WT versus 9 IDH1MUT glioblastoma samples...
July 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28454120/phosphodiesterase-3a-a-new-player-in-development-of-interstitial-cells-of-cajal-and-a-prospective-target-in-gastrointestinal-stromal-tumors-gist
#7
Pierre Vandenberghe, Perrine Hagué, Steven C Hockman, Vincent C Manganiello, Pieter Demetter, Christophe Erneux, Jean-Marie Vanderwinden
We previously identified phosphodiesterase 3A (PDE3A) as a marker for interstitial cells of Cajal (ICC) in adult mouse gut. However, PDE3A expression and function during gut development and in ICC-derived gastrointestinal stromal tumors (GIST) remained unknown. Here we found that PDE3A was expressed throughout ICC development and that ICC density was halved in PDE3A-deficient mice. In the human imatinib-sensitive GIST882 cell line, the PDE3 inhibitor cilostazol halved cell viability (IC50 0.35 μM) and this effect synergized with imatinib (Chou-Talalay's CI50 0...
June 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28381406/exploiting-defective-dna-repair-in-idh-mutant-cancers
#8
(no author information available yet)
Data from a preclinical study suggest rethinking the "oncometabolite hypothesis," which calls for blocking the product of neomorphic IDH1/2 mutations to halt tumor progression. Instead, exploiting the vulnerability of IDH1/2-mutant tumor cells to PARP inhibition, as a result of defective DNA repair, appears to be a more effective strategy that will soon be tested in the clinic.
June 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28375741/isocitrate-dehydrogenase-mutation-and-r-2-hydroxyglutarate-from-basic-discovery-to-therapeutics-development
#9
REVIEW
Lenny Dang, Shin-San Michael Su
The identification of heterozygous mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) in subsets of cancers, including secondary glioblastoma, acute myeloid leukemia, intrahepatic cholangiocarcinoma, and chondrosarcomas, led to intense discovery efforts to delineate the mutations' involvement in carcinogenesis and to develop therapeutics, which we review here. The three IDH isoforms (nicotinamide adenine dinucleotide phosphate-dependent IDH1 and IDH2, and nicotinamide adenine dinucleotide-dependent IDH3) contribute to regulating the circuitry of central metabolism...
June 20, 2017: Annual Review of Biochemistry
https://www.readbyqxmd.com/read/28330869/molecular-mechanisms-of-isocitrate-dehydrogenase-1-idh1-mutations-identified-in-tumors-the-role-of-size-and-hydrophobicity-at-residue-132-on-catalytic-efficiency
#10
Diego Avellaneda Matteo, Adam J Grunseth, Eric R Gonzalez, Stacy L Anselmo, Madison A Kennedy, Precious Moman, David A Scott, An Hoang, Christal D Sohl
Isocitrate dehydrogenase 1 (IDH1) catalyzes the reversible NADP(+)-dependent conversion of isocitrate (ICT) to α-ketoglutarate (αKG) in the cytosol and peroxisomes. Mutations in IDH1 have been implicated in >80% of lower grade gliomas and secondary glioblastomas and primarily affect residue 132, which helps coordinate substrate binding. However, other mutations found in the active site have also been identified in tumors. IDH1 mutations typically result in a loss of catalytic activity, but many also can catalyze a new reaction, the NADPH-dependent reduction of αKG to d-2-hydroxyglutarate (D2HG)...
May 12, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28292433/eto2-glis2-a-chimeric-transcription-factor-drives-leukemogenesis-through-a-neomorphic-transcription-network
#11
COMMENT
Justin C Wheat, Ulrich Steidl
Acute megakaryoblastic leukemia (AMKL) is a heterogeneous disease with a relatively poorly understood pathogenesis. In this issue of Cancer Cell, Thirant and colleagues systematically examine unique transcriptional and functional effects of ETO2-GLIS2, an oncogenic fusion protein frequently encountered in AMKL, and elucidate a therapeutic vulnerability in this poor-prognosis leukemia.
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28270453/activation-of-the-lmo2-oncogene-through-a-somatically-acquired-neomorphic-promoter-in-t-cell-acute-lymphoblastic-leukemia
#12
Sunniyat Rahman, Michael Magnussen, Theresa E León, Nadine Farah, Zhaodong Li, Brian J Abraham, Krisztina Z Alapi, Rachel J Mitchell, Tom Naughton, Adele K Fielding, Arnold Pizzey, Sophia Bustraan, Christopher Allen, Teodora Popa, Karin Pike-Overzet, Laura Garcia-Perez, Rosemary E Gale, David C Linch, Frank J T Staal, Richard A Young, A Thomas Look, Marc R Mansour
Somatic mutations within noncoding genomic regions that aberrantly activate oncogenes have remained poorly characterized. Here we describe recurrent activating intronic mutations of LMO2, a prominent oncogene in T-cell acute lymphoblastic leukemia (T-ALL). Heterozygous mutations were identified in PF-382 and DU.528 T-ALL cell lines in addition to 3.7% of pediatric (6 of 160) and 5.5% of adult (9 of 163) T-ALL patient samples. The majority of indels harbor putative de novo MYB, ETS1, or RUNX1 consensus binding sites...
June 15, 2017: Blood
https://www.readbyqxmd.com/read/28222777/identification-of-somatic-and-germ-line-dicer1-mutations-in-pleuropulmonary-blastoma-cystic-nephroma-and-rhabdomyosarcoma-tumors-within-a-dicer1-syndrome-pedigree
#13
Lorena Fernández-Martínez, José Antonio Villegas, Íñigo Santamaría, Ana S Pitiot, Marta G Alvarado, Soledad Fernández, Héctor Torres, Ángeles Paredes, Pilar Blay, Milagros Balbín
BACKGROUND: DICER1 syndrome is a pediatric cancer predisposition condition causing a variety of tumor types in children and young adults. In this report we studied a family with two relatives presenting a variety of neoplastic conditions at childhood. METHODS: Germ-line mutation screening of the complete coding region of the DICER1 gene in genomic DNA from the proband was performed. The presence of somatic DICER1 mutation and further alterations in driver genes was investigated in genomic DNA obtained from available tumor samples...
February 21, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28207953/sgs1-a-neomorphic-nac52-allele-impairing-post-transcriptional-gene-silencing-through-sgs3-downregulation
#14
Nicolas Butel, Ivan Le Masson, Nathalie Bouteiller, Hervé Vaucheret, Taline Elmayan
Post-transcriptional gene silencing (PTGS) is a defense mechanism that targets invading nucleic acids from endogenous (transposons) or exogenous (pathogens, transgenes) sources. Genetic screens based on the reactivation of silenced transgenes have long been used to identify cellular components and regulators of PTGS. Here we show that the first isolated PTGS-deficient mutant, sgs1, is impaired in the transcription factor NAC52. This mutant exhibits striking similarities to a mutant impaired in the H3K4me3 demethylase JMJ14 isolated from the same genetic screen...
May 2017: Plant Journal: for Cell and Molecular Biology
https://www.readbyqxmd.com/read/28181377/evolution-of-the-hypercarnivorous-dentition-in-mammals-metatheria-eutheria-and-its-bearing-on-the-development-of-tribosphenic-molars
#15
Floréal Solé, Sandrine Ladevèze
One major innovation of mammals is the tribosphenic molar, characterized by the evolution of a neomorphic upper cusp (=protocone) and a lower basin (=talonid) that occlude and provide shearing and crushing functions. This type of molar is an evolutionarily flexible structure that enabled mammals to achieve complex dental adaptations. Among carnivorous mammals, hypercarnivory is a common trend that evolved several times among therians (marsupials, placentals, and stem relatives). Hypercarnivory involves an important simplification of the carnassial molar pattern from the ancestral tribosphenic molar pattern, with the modification of the triangular tooth crown, and the loss of several cusps and cuspids typical of the tribosphenic molar...
February 9, 2017: Evolution & Development
https://www.readbyqxmd.com/read/28155866/reduced-activity-of-sry-and-its-target-enhancer-sox9-tesco-in-a-mouse-species-with-x-y-sex-reversal
#16
Liang Zhao, Alexander Quinn, Ee Ting Ng, Frederic Veyrunes, Peter Koopman
In most eutherian mammals, sex determination is governed by the Y-linked gene Sry, but in African pygmy mice Mus minutoides, Sry action is overridden by a variant X chromosome (X*), yielding X*Y females. We hypothesized that X*Y sex reversal may be underpinned not only by neomorphic X chromosome functionality, but also by a compromised Sry pathway. Here, we show that neither M. minutoides SRY nor its target, the Sox9-TESCO enhancer, had appreciable transcriptional activity in in vitro assays, correlating with sequence degradation compared to Mus musculus counterparts...
February 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28148839/2-hydroxyglutarate-produced-by-neomorphic-idh-mutations-suppresses-homologous-recombination-and-induces-parp-inhibitor-sensitivity
#17
Parker L Sulkowski, Christopher D Corso, Nathaniel D Robinson, Susan E Scanlon, Karin R Purshouse, Hanwen Bai, Yanfeng Liu, Ranjini K Sundaram, Denise C Hegan, Nathan R Fons, Gregory A Breuer, Yuanbin Song, Ketu Mishra-Gorur, Henk M De Feyter, Robin A de Graaf, Yulia V Surovtseva, Maureen Kachman, Stephanie Halene, Murat Günel, Peter M Glazer, Ranjit S Bindra
2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, whereas the latter is produced under pathologic processes such as hypoxia. We report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors...
February 1, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28143851/nan-neomorphic-effects-in-neonatal-anaemia
#18
(no author information available yet)
No abstract text is available yet for this article.
February 1, 2017: Development
https://www.readbyqxmd.com/read/28143845/neomorphic-effects-of-the-neonatal-anemia-nan-eklf-mutation-contribute-to-deficits-throughout-development
#19
Antanas Planutis, Li Xue, Cecelia D Trainor, Mohan Dangeti, Kevin Gillinder, Miroslawa Siatecka, Danitza Nebor, Luanne L Peters, Andrew C Perkins, James J Bieker
Transcription factor control of cell-specific downstream targets can be significantly altered when the controlling factor is mutated. We show that the semi-dominant neonatal anemia (Nan) mutation in the EKLF/KLF1 transcription factor leads to ectopic expression of proteins that are not normally expressed in the red blood cell, leading to systemic effects that exacerbate the intrinsic anemia in the adult and alter correct development in the early embryo. Even when expressed as a heterozygote, the Nan-EKLF protein accomplishes this by direct binding and aberrant activation of genes encoding secreted factors that exert a negative effect on erythropoiesis and iron use...
February 1, 2017: Development
https://www.readbyqxmd.com/read/28124097/pan-mutant-idh1-inhibitor-bay-1436032-for-effective-treatment-of-idh1-mutant-astrocytoma-in-vivo
#20
Stefan Pusch, Sonja Krausert, Viktoria Fischer, Jörg Balss, Martina Ott, Daniel Schrimpf, David Capper, Felix Sahm, Jessica Eisel, Ann-Christin Beck, Manfred Jugold, Viktoria Eichwald, Stefan Kaulfuss, Olaf Panknin, Hartmut Rehwinkel, Katja Zimmermann, Roman C Hillig, Judith Guenther, Luisella Toschi, Roland Neuhaus, Andrea Haegebart, Holger Hess-Stumpp, Markus Bauser, Wolfgang Wick, Andreas Unterberg, Christel Herold-Mende, Michael Platten, Andreas von Deimling
Mutations in codon 132 of isocitrate dehydrogenase (IDH) 1 are frequent in diffuse glioma, acute myeloid leukemia, chondrosarcoma and intrahepatic cholangiocarcinoma. These mutations result in a neomorphic enzyme specificity which leads to a dramatic increase of intracellular D-2-hydroxyglutarate (2-HG) in tumor cells. Therefore, mutant IDH1 protein is a highly attractive target for inhibitory drugs. Here, we describe the development and properties of BAY 1436032, a pan-inhibitor of IDH1 protein with different codon 132 mutations...
April 2017: Acta Neuropathologica
keyword
keyword
38096
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"