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  • 1
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    (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-02-09
    Description: Mutations in IDH1 and IDH2, the genes coding for isocitrate dehydrogenases 1 and 2, are common in several human cancers, including leukemias, and result in overproduction of the (R)-enantiomer of 2-hydroxyglutarate [(R)-2HG]. Elucidation of the role of IDH mutations and (R)-2HG in leukemogenesis has been hampered by a lack of appropriate cell-based models. Here, we show that a canonical IDH1 mutant, IDH1 R132H, promotes cytokine independence and blocks differentiation in hematopoietic cells. These effects can be recapitulated by (R)-2HG, but not (S)-2HG, despite the fact that (S)-2HG more potently inhibits enzymes, such as the 5'-methylcytosine hydroxylase TET2, that have previously been linked to the pathogenesis of IDH mutant tumors. We provide evidence that this paradox relates to the ability of (S)-2HG, but not (R)-2HG, to inhibit the EglN prolyl hydroxylases. Additionally, we show that transformation by (R)-2HG is reversible.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836459/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836459/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Losman, Julie-Aurore -- Looper, Ryan E -- Koivunen, Peppi -- Lee, Sungwoo -- Schneider, Rebekka K -- McMahon, Christine -- Cowley, Glenn S -- Root, David E -- Ebert, Benjamin L -- Kaelin, William G Jr -- P30 DK049216/DK/NIDDK NIH HHS/ -- R01 CA068490/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Mar 29;339(6127):1621-5. doi: 10.1126/science.1231677. Epub 2013 Feb 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23393090" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics/*metabolism ; Glutarates/*metabolism ; *Hematopoiesis ; Humans ; Isocitrate Dehydrogenase/genetics/*metabolism ; Leukemia/*enzymology/genetics ; Models, Biological ; Procollagen-Proline Dioxygenase/*antagonists & inhibitors
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
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    A trinuclear intermediate in the copper-mediated reduction of O2: four electrons from three coppers (1996)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1996-09-27
    Description: The reaction of metal complexes with dioxygen (O2) generally proceeds in 1:1, 21, or 41 (metal:O2) stoichiometry. A discrete, structurally characterized 31 product is presented. This mixed-valence trinuclear copper cluster, which contains copper in the highly oxidized trivalent oxidation state, exhibits O2 bond scission and intriguing structural, spectroscopic, and redox properties. The relevance of this synthetic complex to the reduction of O2 at the trinuclear active sites of multicopper oxidases is discussed.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cole, A P -- Root, D E -- Mukherjee, P -- Solomon, E I -- Stack, T D -- DK31450/DK/NIDDK NIH HHS/ -- GM50730/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 1996 Sep 27;273(5283):1848-50.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Stanford University, Stanford, CA 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8791587" target="_blank"〉PubMed〈/a〉
    Keywords: Copper/chemistry/*metabolism ; Crystallography, X-Ray ; Electrons ; Magnetic Resonance Spectroscopy ; Oxidation-Reduction ; Oxidoreductases/chemistry/metabolism ; Oxygen/*metabolism ; Spectrophotometry, Ultraviolet ; Temperature
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
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    Unbiased reconstruction of a mammalian transcriptional network mediating pathogen responses (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-09-05
    Description: Models of mammalian regulatory networks controlling gene expression have been inferred from genomic data but have largely not been validated. We present an unbiased strategy to systematically perturb candidate regulators and monitor cellular transcriptional responses. We applied this approach to derive regulatory networks that control the transcriptional response of mouse primary dendritic cells to pathogens. Our approach revealed the regulatory functions of 125 transcription factors, chromatin modifiers, and RNA binding proteins, which enabled the construction of a network model consisting of 24 core regulators and 76 fine-tuners that help to explain how pathogen-sensing pathways achieve specificity. This study establishes a broadly applicable, comprehensive, and unbiased approach to reveal the wiring and functions of a regulatory network controlling a major transcriptional response in primary mammalian cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879337/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879337/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Amit, Ido -- Garber, Manuel -- Chevrier, Nicolas -- Leite, Ana Paula -- Donner, Yoni -- Eisenhaure, Thomas -- Guttman, Mitchell -- Grenier, Jennifer K -- Li, Weibo -- Zuk, Or -- Schubert, Lisa A -- Birditt, Brian -- Shay, Tal -- Goren, Alon -- Zhang, Xiaolan -- Smith, Zachary -- Deering, Raquel -- McDonald, Rebecca C -- Cabili, Moran -- Bernstein, Bradley E -- Rinn, John L -- Meissner, Alex -- Root, David E -- Hacohen, Nir -- Regev, Aviv -- DP1 OD003958/OD/NIH HHS/ -- DP1 OD003958-01/OD/NIH HHS/ -- DP2 OD002230/OD/NIH HHS/ -- DP2 OD002230-01/OD/NIH HHS/ -- R21 AI071060/AI/NIAID NIH HHS/ -- R21 AI071060-01/AI/NIAID NIH HHS/ -- R21 AI71060/AI/NIAID NIH HHS/ -- S10 RR026688/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2009 Oct 9;326(5950):257-63. doi: 10.1126/science.1179050. Epub 2009 Sep 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19729616" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacteria/*immunology ; Chromatin Assembly and Disassembly ; DNA, Single-Stranded/immunology ; Dendritic Cells/*immunology/*metabolism ; Feedback, Physiological ; Gene Expression Profiling ; *Gene Expression Regulation ; *Gene Regulatory Networks ; Inflammation/immunology/*metabolism ; Lipopeptides/immunology ; Lipopolysaccharides/immunology ; Mice ; Mice, Inbred C57BL ; Poly I-C/immunology ; RNA-Binding Proteins/metabolism ; Toll-Like Receptors/agonists ; Transcription Factors/metabolism ; Transcription, Genetic ; Viruses/*immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
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    Genome-scale CRISPR-Cas9 knockout screening in human cells (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-12-18
    Description: The simplicity of programming the CRISPR (clustered regularly interspaced short palindromic repeats)-associated nuclease Cas9 to modify specific genomic loci suggests a new way to interrogate gene function on a genome-wide scale. We show that lentiviral delivery of a genome-scale CRISPR-Cas9 knockout (GeCKO) library targeting 18,080 genes with 64,751 unique guide sequences enables both negative and positive selection screening in human cells. First, we used the GeCKO library to identify genes essential for cell viability in cancer and pluripotent stem cells. Next, in a melanoma model, we screened for genes whose loss is involved in resistance to vemurafenib, a therapeutic RAF inhibitor. Our highest-ranking candidates include previously validated genes NF1 and MED12, as well as novel hits NF2, CUL3, TADA2B, and TADA1. We observe a high level of consistency between independent guide RNAs targeting the same gene and a high rate of hit confirmation, demonstrating the promise of genome-scale screening with Cas9.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089965/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089965/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shalem, Ophir -- Sanjana, Neville E -- Hartenian, Ella -- Shi, Xi -- Scott, David A -- Mikkelsen, Tarjei S -- Heckl, Dirk -- Ebert, Benjamin L -- Root, David E -- Doench, John G -- Zhang, Feng -- 1DP1-MH100706/DP/NCCDPHP CDC HHS/ -- 1R01-DK097768/DK/NIDDK NIH HHS/ -- DP1 MH100706/MH/NIMH NIH HHS/ -- R01 DK097768/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2014 Jan 3;343(6166):84-7. doi: 10.1126/science.1247005. Epub 2013 Dec 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24336571" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/genetics ; Caspase 9/*genetics ; Cell Survival/*genetics ; *Clustered Regularly Interspaced Short Palindromic Repeats ; Cullin Proteins/genetics ; Drug Resistance, Neoplasm/*genetics ; Gene Knockout Techniques ; Gene Library ; Genes, Neurofibromatosis 1 ; Genes, Neurofibromatosis 2 ; Genetic Loci ; Genetic Testing/*methods ; Genome-Wide Association Study ; Humans ; Indoles/therapeutic use ; Lentivirus ; Mediator Complex/genetics ; Melanoma/drug therapy/*genetics ; Pluripotent Stem Cells/*metabolism ; Protein Kinase Inhibitors/therapeutic use ; Selection, Genetic ; Sulfonamides/therapeutic use ; Transcription Factors/genetics ; raf Kinases/antagonists & inhibitors
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
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    Malaria. A forward genetic screen identifies erythrocyte CD55 as essential for Plasmodium falciparum invasion (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-05-09
    Description: Efforts to identify host determinants for malaria have been hindered by the absence of a nucleus in erythrocytes, which precludes genetic manipulation in the cell in which the parasite replicates. We used cultured red blood cells derived from hematopoietic stem cells to carry out a forward genetic screen for Plasmodium falciparum host determinants. We found that CD55 is an essential host factor for P. falciparum invasion. CD55-null erythrocytes were refractory to invasion by all isolates of P. falciparum because parasites failed to attach properly to the erythrocyte surface. Thus, CD55 is an attractive target for the development of malaria therapeutics. Hematopoietic stem cell-based forward genetic screens may be valuable for the identification of additional host determinants of malaria pathogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465434/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465434/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Egan, Elizabeth S -- Jiang, Rays H Y -- Moechtar, Mischka A -- Barteneva, Natasha S -- Weekes, Michael P -- Nobre, Luis V -- Gygi, Steven P -- Paulo, Joao A -- Frantzreb, Charles -- Tani, Yoshihiko -- Takahashi, Junko -- Watanabe, Seishi -- Goldberg, Jonathan -- Paul, Aditya S -- Brugnara, Carlo -- Root, David E -- Wiegand, Roger C -- Doench, John G -- Duraisingh, Manoj T -- 100140/Wellcome Trust/United Kingdom -- 1K08AI103034-01A1/AI/NIAID NIH HHS/ -- K01 DK098285/DK/NIDDK NIH HHS/ -- K01DK098285/DK/NIDDK NIH HHS/ -- K08 AI103034/AI/NIAID NIH HHS/ -- K12-HD000850/HD/NICHD NIH HHS/ -- R01AI091787/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2015 May 8;348(6235):711-4. doi: 10.1126/science.aaa3526.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA. Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA. ; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA. Department of Global Health and Center for Drug Discovery and Innovation, University of South Florida, Tampa, FL, USA. ; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA. ; Department of Pediatrics, Harvard Medical School and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA. ; Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK. ; Department of Cell Biology, Harvard Medical School, Boston, MA, USA. ; Japanese Red Cross Kinki Block Blood Center, Osaka, Japan. ; Japanese Red Cross Kyushu Block Blood Center, Fukuoka, Japan. ; Department of Laboratory Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. ; The Broad Institute of Harvard and Massachussetts Insititute of Technology, Cambridge, MA, USAA. ; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA. The Broad Institute of Harvard and Massachussetts Insititute of Technology, Cambridge, MA, USAA. mduraisi@hsph.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25954012" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD44/genetics ; Antigens, CD55/*genetics ; Cell Differentiation/genetics ; Cells, Cultured ; Erythrocytes/cytology/metabolism/*parasitology ; Genetic Testing ; Hematopoietic Stem Cells/cytology ; Host-Parasite Interactions/*genetics ; Humans ; Malaria, Falciparum/*genetics/*parasitology ; Plasmodium falciparum/*pathogenicity ; RNA, Small Interfering/genetics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
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    Identification of an oncogenic RAB protein (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-09-05
    Description: In a short hairpin RNA screen for genes that affect AKT phosphorylation, we identified the RAB35 small guanosine triphosphatase (GTPase)-a protein previously implicated in endomembrane trafficking-as a regulator of the phosphatidylinositol 3'-OH kinase (PI3K) pathway. Depletion of RAB35 suppresses AKT phosphorylation in response to growth factors, whereas expression of a dominant active GTPase-deficient mutant of RAB35 constitutively activates the PI3K/AKT pathway. RAB35 functions downstream of growth factor receptors and upstream of PDK1 and mTORC2 and copurifies with PI3K in immunoprecipitation assays. Two somatic RAB35 mutations found in human tumors generate alleles that constitutively activate PI3K/AKT signaling, suppress apoptosis, and transform cells in a PI3K-dependent manner. Furthermore, oncogenic RAB35 is sufficient to drive platelet-derived growth factor receptor alpha to LAMP2-positive endomembranes in the absence of ligand, suggesting that there may be latent oncogenic potential in dysregulated endomembrane trafficking.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600465/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600465/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wheeler, Douglas B -- Zoncu, Roberto -- Root, David E -- Sabatini, David M -- Sawyers, Charles L -- 1DP2CA195761-01/CA/NCI NIH HHS/ -- AI47389/AI/NIAID NIH HHS/ -- CA092629/CA/NCI NIH HHS/ -- CA103866/CA/NCI NIH HHS/ -- CA155169/CA/NCI NIH HHS/ -- GM07739/GM/NIGMS NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R01 CA155169/CA/NCI NIH HHS/ -- R01 CA193837/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2015 Oct 9;350(6257):211-7. doi: 10.1126/science.aaa4903. Epub 2015 Sep 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. Weill Cornell/Rockefeller University/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY 10021, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA. ; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA. David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. sawyersc@mskcc.org sabatini@wi.mit.edu. ; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. sawyersc@mskcc.org sabatini@wi.mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26338797" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Cell Line, Tumor ; Gene Deletion ; Humans ; Immunoprecipitation ; Lysosomal-Associated Membrane Protein 2/metabolism ; Multiprotein Complexes/metabolism ; Mutation ; Neoplasms/genetics/*metabolism/pathology ; Oncogene Proteins/genetics/*metabolism ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphorylation/genetics ; Protein Transport ; Protein-Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; RNA Interference ; RNA, Small Interfering/genetics ; Receptor, Platelet-Derived Growth Factor alpha/metabolism ; TOR Serine-Threonine Kinases/metabolism ; rab GTP-Binding Proteins/genetics/*metabolism
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  • 7
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    MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-26
    Description: The discovery of cancer dependencies has the potential to inform therapeutic strategies and to identify putative drug targets. Integrating data from comprehensive genomic profiling of cancer cell lines and from functional characterization of cancer cell dependencies, we discovered that loss of the enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77. MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor gene, CDKN2A. We observed increased intracellular concentrations of methylthioadenosine (MTA, the metabolite cleaved by MTAP) in cells harboring MTAP deletions. Furthermore, MTA specifically inhibited PRMT5 enzymatic activity. Administration of either MTA or a small-molecule PRMT5 inhibitor showed a modest preferential impairment of cell viability for MTAP-null cancer cell lines compared with isogenic MTAP-expressing counterparts. Together, our findings reveal PRMT5 as a potential vulnerability across multiple cancer lineages augmented by a common "passenger" genomic alteration.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kryukov, Gregory V -- Wilson, Frederick H -- Ruth, Jason R -- Paulk, Joshiawa -- Tsherniak, Aviad -- Marlow, Sara E -- Vazquez, Francisca -- Weir, Barbara A -- Fitzgerald, Mark E -- Tanaka, Minoru -- Bielski, Craig M -- Scott, Justin M -- Dennis, Courtney -- Cowley, Glenn S -- Boehm, Jesse S -- Root, David E -- Golub, Todd R -- Clish, Clary B -- Bradner, James E -- Hahn, William C -- Garraway, Levi A -- KL2 TR001100/TR/NCATS NIH HHS/ -- U01 CA176058/CA/NCI NIH HHS/ -- U54 CA112962/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2016 Mar 11;351(6278):1214-8. doi: 10.1126/science.aad5214. Epub 2016 Feb 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. levi_garraway@dfci.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912360" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line, Tumor ; Deoxyadenosines/metabolism/pharmacology ; Enzyme Inhibitors/pharmacology ; Gene Deletion ; Humans ; Isoquinolines/pharmacology ; Neoplasms/*drug therapy/enzymology ; Protein-Arginine N-Methyltransferases/antagonists & ; inhibitors/genetics/*metabolism ; Purine-Nucleoside Phosphorylase/genetics/*metabolism ; Pyrimidines/pharmacology ; Thionucleosides/metabolism/pharmacology ; Transcription Factors
    Print ISSN: 0036-8075
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  • 8
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    A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies (2019)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2019
    Description: 〈p〉〈i〉TP53〈/i〉, which encodes the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, are enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We used CRISPR-Cas9 to generate isogenic human leukemia cell lines of the most common 〈i〉TP53〈/i〉 missense mutations. Functional, DNA-binding, and transcriptional analyses revealed loss of function but no GOF effects. Comprehensive mutational scanning of p53 single–amino acid variants demonstrated that missense variants in the DNA-binding domain exert a dominant-negative effect (DNE). In mice, the DNE of p53 missense variants confers a selective advantage to hematopoietic cells on DNA damage. Analysis of clinical outcomes in patients with acute myeloid leukemia showed no evidence of GOF for 〈i〉TP53〈/i〉 missense mutations. Thus, a DNE is the primary unit of selection for 〈i〉TP53〈/i〉 missense mutations in myeloid malignancies.〈/p〉
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