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https://www.readbyqxmd.com/read/29184081/allosteric-inhibitor-remotely-modulates-the-conformation-of-the-orthestric-pockets-in-mutant-idh2-r140q
#1
Jiao Chen, Jie Yang, Xianqiang Sun, Zhongming Wang, Xiaolan Cheng, Wuguang Lu, Xueting Cai, Chunping Hu, Xu Shen, Peng Cao
Neomorphic mutation R140Q in the metabolic enzyme isocitrate dehydrogenase 2 (IDH2) is found to be a driver mutation in cancers. Recent studies revealed that allosteric inhibitors could selectively inhibit IDH2/R140Q and induce differentiation of TF-1 erythroleukemia and primary human AML cells. However, the allosteric inhibition mechanism is not very clear. Here, we report the results from computational studies that AGI-6780 binds tightly with the divalent cation binding helices at the homodimer interface and prevents the transition of IDH2/R140Q homodimer to a closed conformation that is required for catalysis, resulting in the decrease of the binding free energy of NADPHs...
November 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29174564/crispr-cas9-engineered-osteogenesis-imperfecta-type-v-leads-to-severe-skeletal-deformities-and-perinatal-lethality-in-mice
#2
Frank Rauch, Yeqing Geng, Lisa Lamplugh, Bahareh Hekmatnejad, Marie-Hélène Gaumond, Janice Penney, Yojiro Yamanaka, Pierre Moffatt
Osteogenesis imperfecta (OI) type V is caused by an autosomal dominant mutation in the IFITM5 gene, also known as BRIL. The c.-14C>T mutation in the 5'UTR of BRIL creates a novel translational start site adding 5 residues (MALEP) in frame with the natural coding of BRIL. A neomorphic function has been proposed for the MALEP-BRIL but the mechanisms at play are still unknown. In order to further understand the effects of MALEP-BRIL in vivo, we generated a knockin (KI) mouse model having the exact genetic -14C>T replica of patients with OI type V...
November 22, 2017: Bone
https://www.readbyqxmd.com/read/29097607/adaptive-evolution-of-the-gdh2-allosteric-domain-promotes-gliomagenesis-by-resolving-idh1-r132h-induced-metabolic-liabilities
#3
Matthew S Waitkus, Christopher J Pirozzi, Casey J Moure, Bill H Diplas, Landon J Hansen, Austin B Carpenter, Rui Yang, Zhaohui Wang, Brian O Ingram, Edward D Karoly, Robert P Mohney, Ivan Spasojeic, Roger E McLendon, Henry S Friedman, Yiping He, Darell D Bigner, Hai Yan
Hot-spot mutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in a number of human cancers and confer a neomorphic enzyme activity that catalyzes the conversion of α-ketoglutarate (αKG) to the oncometabolite D-(2)-hydroxyglutarate (D2HG). In malignant gliomas, IDH1(R132H) expression induces widespread metabolic reprogramming, possibly requiring compensatory mechanisms to sustain the normal biosynthetic requirements of actively proliferating tumor cells. We used genetically engineered mouse models of glioma and quantitative metabolomics to investigate IDH1(R132H)-dependent metabolic reprogramming and its potential to induce biosynthetic liabilities that can be exploited for glioma therapy...
November 2, 2017: Cancer Research
https://www.readbyqxmd.com/read/29091765/low-grade-astrocytoma-mutations-in-idh1-p53-and-atrx-cooperate-to-block-differentiation-of-human-neural-stem-cells-via-repression-of-sox2
#4
Aram S Modrek, Danielle Golub, Themasap Khan, Devin Bready, Jod Prado, Christopher Bowman, Jingjing Deng, Guoan Zhang, Pedro P Rocha, Ramya Raviram, Charalampos Lazaris, James M Stafford, Gary LeRoy, Michael Kader, Joravar Dhaliwal, N Sumru Bayin, Joshua D Frenster, Jonathan Serrano, Luis Chiriboga, Rabaa Baitalmal, Gouri Nanjangud, Andrew S Chi, John G Golfinos, Jing Wang, Matthias A Karajannis, Richard A Bonneau, Danny Reinberg, Aristotelis Tsirigos, David Zagzag, Matija Snuderl, Jane A Skok, Thomas A Neubert, Dimitris G Placantonakis
Low-grade astrocytomas (LGAs) carry neomorphic mutations in isocitrate dehydrogenase (IDH) concurrently with P53 and ATRX loss. To model LGA formation, we introduced R132H IDH1, P53 shRNA, and ATRX shRNA into human neural stem cells (NSCs). These oncogenic hits blocked NSC differentiation, increased invasiveness in vivo, and led to a DNA methylation and transcriptional profile resembling IDH1 mutant human LGAs. The differentiation block was caused by transcriptional silencing of the transcription factor SOX2 secondary to disassociation of its promoter from a putative enhancer...
October 31, 2017: Cell Reports
https://www.readbyqxmd.com/read/29090344/the-role-of-mutant-idh1-and-idh2-inhibitors-in-the-treatment-of-acute-myeloid-leukemia
#5
REVIEW
Samah Nassereddine, Coen J Lap, Faysal Haroun, Imad Tabbara
For decades, researchers have looked into the pathophysiology of acute myeloid leukemia (AML). With the advances in molecular techniques, the two-hit hypothesis was replaced by a multi-hit model, which also emphasizes the importance of aberrant epigenetic regulation in the pathogenesis of AML. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert α-ketoglutarate (αKG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple αKG-dependent dioxygenases...
October 31, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/29044203/neomorphosis-and-heterochrony-of-skull-shape-in-dog-domestication
#6
Madeleine Geiger, Allowen Evin, Marcelo R Sánchez-Villagra, Dominic Gascho, Cornelia Mainini, Christoph P E Zollikofer
The overall similarity of the skull shape of some dog breeds with that of juvenile wolves begs the question if and how ontogenetic changes such as paedomorphosis (evolutionary juvenilisation) played a role in domestication. Here we test for changes in patterns of development and growth during dog domestication. We present the first geometric morphometric study using ontogenetic series of dog and wolf crania, and samples of dogs with relatively ancestral morphology and from different time periods. We show that patterns of juvenile-to-adult morphological change are largely similar in wolves and domestic dogs, but differ in two ways...
October 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29025583/a-rare-case-of-pediatric-lipoma-with-t-9-12-p22-q14-and-evidence-of-hmga2-nfib-gene-fusion
#7
Melanie Lacaria, Dina El Demellawy, Jean McGowan-Jordan
Lipoma is a benign tumor, typically of adulthood, with characteristic cytogenetic findings, including rearrangement of 12q13-15; these rearrangements often lead to the fusion of the HMGA2 gene at this locus to the transcriptional regulatory domain of its fusion partner, resulting in neomorphic activity that presumably facilitates the neoplastic process. Herein, we report a rare case of pediatric lipoma with t(9;12)(p22;q14) and evidence of HMGA2-NFIB gene fusion in a 9 year-old boy. This case provides further evidence of the link between NFIB rearrangement and early-onset, deep-seated lipomatous tumors...
October 2017: Cancer Genetics
https://www.readbyqxmd.com/read/28931065/chlamydomonas-fap265-is-a-tubulin-polymerization-promoting-protein-essential-for-flagellar-reassembly-and-hatching-of-daughter-cells-from-the-sporangium
#8
Damayanti Tammana, Trinadh Venkata Satish Tammana
Tubulin polymerization promoting proteins (TPPPs) belong to a family of neomorphic moon lighting proteins, involved in various physiological and pathological conditions. In physiological conditions, TPPPs play an important role in microtubule dynamics regulating mitotic spindle assembly and in turn cell proliferation. In pathological situations, TPPPs interact with α-synuclein and β-amyloid and promote their aggregation leading to Parkinson's disease and multiple system atrophy. Orthologs of TPPP family proteins were identified in ciliary proteomes from various organisms including Chlamydomonas but their role in ciliogenesis was not known...
2017: PloS One
https://www.readbyqxmd.com/read/28855157/h3-k27m-i-mutations-promote-context-dependent-transformation-in-acute-myeloid-leukemia-with-runx1-alterations
#9
Bernhard Lehnertz, Yu Wei Zhang, Isabel Boivin, Nadine Mayotte, Elisa Tomellini, Jalila Chagraoui, Vincent-Philippe Lavallée, Josée Hébert, Guy Sauvageau
Neomorphic missense mutations affecting crucial lysine residues in histone H3 genes significantly contribute to a variety of solid cancers. Despite the high prevalence of H3(K27M) mutations in pediatric glioblastoma and their well-established impact on global histone H3 lysine 27 di and trimethylation (H3K27me2/3), the relevance of these mutations has not been studied in acute myeloid leukemia (AML). Here, we report the first identification of H3(K27M) and H3(K27I) mutations in AML patients. We find that these lesions are major determinants of reduced H3K27me2/3 in these patients and that they associate with common aberrations in the RUNX1 gene...
August 30, 2017: Blood
https://www.readbyqxmd.com/read/28844694/cancer-specific-retargeting-of-baf-complexes-by-a-prion-like-domain
#10
Gaylor Boulay, Gabriel J Sandoval, Nicolo Riggi, Sowmya Iyer, Rémi Buisson, Beverly Naigles, Mary E Awad, Shruthi Rengarajan, Angela Volorio, Matthew J McBride, Liliane C Broye, Lee Zou, Ivan Stamenkovic, Cigall Kadoch, Miguel N Rivera
Alterations in transcriptional regulators can orchestrate oncogenic gene expression programs in cancer. Here, we show that the BRG1/BRM-associated factor (BAF) chromatin remodeling complex, which is mutated in over 20% of human tumors, interacts with EWSR1, a member of a family of proteins with prion-like domains (PrLD) that are frequent partners in oncogenic fusions with transcription factors. In Ewing sarcoma, we find that the BAF complex is recruited by the EWS-FLI1 fusion protein to tumor-specific enhancers and contributes to target gene activation...
September 21, 2017: Cell
https://www.readbyqxmd.com/read/28835377/distinct-effects-of-tubulin-isotype-mutations-on-neurite-growth-in-caenorhabditis-elegans
#11
Chaogu Zheng, Margarete Diaz-Cuadros, Ken C Q Nguyen, David H Hall, Martin Chalfie
Tubulins, the building block of microtubules (MTs), play a critical role in both supporting and regulating neurite growth. Eukaryotic genomes contain multiple tubulin isotypes, and their missense mutations cause a range of neurodevelopmental defects. Using the Caenorhabditis elegans touch receptor neurons, we analyzed the effects of 67 tubulin missense mutations on neurite growth. Three types of mutations emerged: 1) loss-of-function mutations, which cause mild defects in neurite growth; 2) antimorphic mutations, which map to the GTP binding site and intradimer and interdimer interfaces, significantly reduce MT stability, and cause severe neurite growth defects; and 3) neomorphic mutations, which map to the exterior surface, increase MT stability, and cause ectopic neurite growth...
October 15, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28705010/isocitrate-dehydrogenase-mutation-as-a-therapeutic-target-in-gliomas
#12
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
#13
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
#14
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...
October 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
#15
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
#16
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
#17
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
#18
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
#19
(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
#20
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
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