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  • Cell Line, Tumor  (16)
  • Nature Publishing Group (NPG)  (16)
  • American Chemical Society
  • Blackwell Science Pty
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  • 1
    Publication Date: 2012-08-17
    Description: Inactivation of tumour-suppressor genes by homozygous deletion is a prototypic event in the cancer genome, yet such deletions often encompass neighbouring genes. We propose that homozygous deletions in such passenger genes can expose cancer-specific therapeutic vulnerabilities when the collaterally deleted gene is a member of a functionally redundant family of genes carrying out an essential function. The glycolytic gene enolase 1 (ENO1) in the 1p36 locus is deleted in glioblastoma (GBM), which is tolerated by the expression of ENO2. Here we show that short-hairpin-RNA-mediated silencing of ENO2 selectively inhibits growth, survival and the tumorigenic potential of ENO1-deleted GBM cells, and that the enolase inhibitor phosphonoacetohydroxamate is selectively toxic to ENO1-deleted GBM cells relative to ENO1-intact GBM cells or normal astrocytes. The principle of collateral vulnerability should be applicable to other passenger-deleted genes encoding functionally redundant essential activities and provide an effective treatment strategy for cancers containing such genomic events.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712624/" 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/PMC3712624/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Muller, Florian L -- Colla, Simona -- Aquilanti, Elisa -- Manzo, Veronica E -- Genovese, Giannicola -- Lee, Jaclyn -- Eisenson, Daniel -- Narurkar, Rujuta -- Deng, Pingna -- Nezi, Luigi -- Lee, Michelle A -- Hu, Baoli -- Hu, Jian -- Sahin, Ergun -- Ong, Derrick -- Fletcher-Sananikone, Eliot -- Ho, Dennis -- Kwong, Lawrence -- Brennan, Cameron -- Wang, Y Alan -- Chin, Lynda -- DePinho, Ronald A -- 3 P01 CA095616-08S1/CA/NCI NIH HHS/ -- 57006984/Howard Hughes Medical Institute/ -- P01 CA095616/CA/NCI NIH HHS/ -- P01CA95616/CA/NCI NIH HHS/ -- T32-CA009361/CA/NCI NIH HHS/ -- England -- Nature. 2012 Aug 16;488(7411):337-42. doi: 10.1038/nature11331.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22895339" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents/pharmacology/therapeutic use ; Biomarkers, Tumor/deficiency/genetics ; Brain Neoplasms/*drug therapy/*genetics/pathology ; Cell Line, Tumor ; Cell Proliferation ; Chromosomes, Human, Pair 1/genetics ; DNA-Binding Proteins/deficiency/genetics ; Enzyme Inhibitors ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Genes, Essential/*genetics ; Genes, Tumor Suppressor ; Glioblastoma/*drug therapy/*genetics/pathology ; Homozygote ; Humans ; Hydroxamic Acids/pharmacology/therapeutic use ; Mice ; Molecular Targeted Therapy/*methods ; Neoplasm Transplantation ; Phosphonoacetic Acid/analogs & derivatives/pharmacology/therapeutic use ; Phosphopyruvate Hydratase/antagonists & inhibitors/deficiency/genetics/metabolism ; RNA, Small Interfering/genetics ; Sequence Deletion/*genetics ; Tumor Suppressor Proteins/deficiency/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2011-07-15
    Description: Malignant transformation, driven by gain-of-function mutations in oncogenes and loss-of-function mutations in tumour suppressor genes, results in cell deregulation that is frequently associated with enhanced cellular stress (for example, oxidative, replicative, metabolic and proteotoxic stress, and DNA damage). Adaptation to this stress phenotype is required for cancer cells to survive, and consequently cancer cells may become dependent upon non-oncogenes that do not ordinarily perform such a vital function in normal cells. Thus, targeting these non-oncogene dependencies in the context of a transformed genotype may result in a synthetic lethal interaction and the selective death of cancer cells. Here we used a cell-based small-molecule screening and quantitative proteomics approach that resulted in the unbiased identification of a small molecule that selectively kills cancer cells but not normal cells. Piperlongumine increases the level of reactive oxygen species (ROS) and apoptotic cell death in both cancer cells and normal cells engineered to have a cancer genotype, irrespective of p53 status, but it has little effect on either rapidly or slowly dividing primary normal cells. Significant antitumour effects are observed in piperlongumine-treated mouse xenograft tumour models, with no apparent toxicity in normal mice. Moreover, piperlongumine potently inhibits the growth of spontaneously formed malignant breast tumours and their associated metastases in mice. Our results demonstrate the ability of a small molecule to induce apoptosis selectively in cells that have a cancer genotype, by targeting a non-oncogene co-dependency acquired through the expression of the cancer genotype in response to transformation-induced oxidative stress.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316487/" 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/PMC3316487/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Raj, Lakshmi -- Ide, Takao -- Gurkar, Aditi U -- Foley, Michael -- Schenone, Monica -- Li, Xiaoyu -- Tolliday, Nicola J -- Golub, Todd R -- Carr, Steven A -- Shamji, Alykhan F -- Stern, Andrew M -- Mandinova, Anna -- Schreiber, Stuart L -- Lee, Sam W -- 5 RC2 CA148399-02/CA/NCI NIH HHS/ -- CA080058/CA/NCI NIH HHS/ -- CA085681/CA/NCI NIH HHS/ -- CA127247/CA/NCI NIH HHS/ -- CA142805/CA/NCI NIH HHS/ -- P01 CA080058/CA/NCI NIH HHS/ -- P01 CA080058-02/CA/NCI NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- R01 CA085681/CA/NCI NIH HHS/ -- R01 CA085681-06/CA/NCI NIH HHS/ -- R01 CA142805/CA/NCI NIH HHS/ -- R01 CA142805-01/CA/NCI NIH HHS/ -- RL1CA133834/CA/NCI NIH HHS/ -- RL1GM084437/GM/NIGMS NIH HHS/ -- RL1HG004671/HG/NHGRI NIH HHS/ -- UL1RR024924/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jul 13;475(7355):231-4. doi: 10.1038/nature10167.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Building 149 13th Street, Charlestown, Massachusetts 02129, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21753854" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis/*drug effects ; Breast Neoplasms/*drug therapy/genetics/metabolism/*pathology ; Cell Line ; Cell Line, Tumor ; Cell Transformation, Neoplastic ; Comet Assay ; DNA Damage/drug effects ; Dioxolanes/adverse effects/chemistry/*pharmacology ; Genotype ; Mice ; Neoplasm Metastasis/drug therapy/pathology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/*metabolism ; Small Molecule Libraries/chemistry ; Xenograft Model Antitumor Assays
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2012-02-22
    Description: The identification of succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH) mutations in human cancers has rekindled the idea that altered cellular metabolism can transform cells. Inactivating SDH and FH mutations cause the accumulation of succinate and fumarate, respectively, which can inhibit 2-oxoglutarate (2-OG)-dependent enzymes, including the EGLN prolyl 4-hydroxylases that mark the hypoxia inducible factor (HIF) transcription factor for polyubiquitylation and proteasomal degradation. Inappropriate HIF activation is suspected of contributing to the pathogenesis of SDH-defective and FH-defective tumours but can suppress tumour growth in some other contexts. IDH1 and IDH2, which catalyse the interconversion of isocitrate and 2-OG, are frequently mutated in human brain tumours and leukaemias. The resulting mutants have the neomorphic ability to convert 2-OG to the (R)-enantiomer of 2-hydroxyglutarate ((R)-2HG). Here we show that (R)-2HG, but not (S)-2HG, stimulates EGLN activity, leading to diminished HIF levels, which enhances the proliferation and soft agar growth of human astrocytes. These findings define an enantiomer-specific mechanism by which the (R)-2HG that accumulates in IDH mutant brain tumours promotes transformation and provide a justification for exploring EGLN inhibition as a potential treatment strategy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3656605/" 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/PMC3656605/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Koivunen, Peppi -- Lee, Sungwoo -- Duncan, Christopher G -- Lopez, Giselle -- Lu, Gang -- Ramkissoon, Shakti -- Losman, Julie A -- Joensuu, Paivi -- Bergmann, Ulrich -- Gross, Stefan -- Travins, Jeremy -- Weiss, Samuel -- Looper, Ryan -- Ligon, Keith L -- Verhaak, Roel G W -- Yan, Hai -- Kaelin, William G Jr -- R01 CA068490/CA/NCI NIH HHS/ -- R01 CA140316/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Feb 15;483(7390):484-8. doi: 10.1038/nature10898.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biocenter Oulu, Department of Medical Biochemistry and Molecular Biology, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22343896" target="_blank"〉PubMed〈/a〉
    Keywords: Astrocytes/cytology/drug effects/metabolism ; Cell Line ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Transformation, Neoplastic/*drug effects/genetics/*metabolism ; Dioxygenases/genetics/*metabolism ; Enzyme Activation/drug effects ; Glioma/enzymology/genetics/metabolism/pathology ; Glutarates/*chemistry/metabolism/*pharmacology ; Humans ; Hypoxia-Inducible Factor 1/metabolism ; Hypoxia-Inducible Factor-Proline Dioxygenases ; Isocitrate Dehydrogenase/genetics/metabolism ; Nuclear Proteins/genetics/*metabolism ; Oncogenes ; Procollagen-Proline Dioxygenase/genetics/*metabolism
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2012-09-21
    Description: The AP1 transcription factor Batf3 is required for homeostatic development of CD8alpha(+) classical dendritic cells that prime CD8 T-cell responses against intracellular pathogens. Here we identify an alternative, Batf3-independent pathway in mice for CD8alpha(+) dendritic cell development operating during infection with intracellular pathogens and mediated by the cytokines interleukin (IL)-12 and interferon-gamma. This alternative pathway results from molecular compensation for Batf3 provided by the related AP1 factors Batf, which also functions in T and B cells, and Batf2 induced by cytokines in response to infection. Reciprocally, physiological compensation between Batf and Batf3 also occurs in T cells for expression of IL-10 and CTLA4. Compensation among BATF factors is based on the shared capacity of their leucine zipper domains to interact with non-AP1 factors such as IRF4 and IRF8 to mediate cooperative gene activation. Conceivably, manipulating this alternative pathway of dendritic cell development could be of value in augmenting immune responses to vaccines.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482832/" 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/PMC3482832/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tussiwand, Roxane -- Lee, Wan-Ling -- Murphy, Theresa L -- Mashayekhi, Mona -- KC, Wumesh -- Albring, Jorn C -- Satpathy, Ansuman T -- Rotondo, Jeffrey A -- Edelson, Brian T -- Kretzer, Nicole M -- Wu, Xiaodi -- Weiss, Leslie A -- Glasmacher, Elke -- Li, Peng -- Liao, Wei -- Behnke, Michael -- Lam, Samuel S K -- Aurthur, Cora T -- Leonard, Warren J -- Singh, Harinder -- Stallings, Christina L -- Sibley, L David -- Schreiber, Robert D -- Murphy, Kenneth M -- AI076427-02/AI/NIAID NIH HHS/ -- P30 CA91842/CA/NCI NIH HHS/ -- R01 AI036629/AI/NIAID NIH HHS/ -- R01 AI076427/AI/NIAID NIH HHS/ -- R01 CA043059/CA/NCI NIH HHS/ -- T32 AI007163/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Oct 25;490(7421):502-7. doi: 10.1038/nature11531. Epub 2012 Sep 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22992524" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigen Presentation ; Antigens, CD/metabolism ; Antigens, CD8/immunology/metabolism ; Basic-Leucine Zipper Transcription ; Factors/chemistry/deficiency/genetics/*metabolism ; CD4-Positive T-Lymphocytes/cytology/immunology ; CTLA-4 Antigen/metabolism ; Cell Differentiation ; Cell Line, Tumor ; Cell Lineage ; Dendritic Cells/*cytology/immunology/*metabolism ; Female ; Fibrosarcoma/immunology/metabolism/pathology ; Gene Expression Regulation ; Integrin alpha Chains/metabolism ; Interferon Regulatory Factors/deficiency/genetics/*metabolism ; Interleukin-10/metabolism ; Interleukin-12/immunology/metabolism ; Leucine Zippers ; Male ; Mice ; Mice, Inbred C57BL ; Neoplasm Transplantation ; Oncogene Protein p65(gag-jun)/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Repressor Proteins/deficiency/genetics ; T-Lymphocytes, Helper-Inducer/cytology/immunology/metabolism ; Toxoplasma/immunology
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2012-06-09
    Description: Protein synthesis involves the translation of ribonucleic acid information into proteins, the building blocks of life. The initial step of protein synthesis is the binding of the eukaryotic translation initiation factor 4E (eIF4E) to the 7-methylguanosine (m(7)-GpppG) 5' cap of messenger RNAs. Low oxygen tension (hypoxia) represses cap-mediated translation by sequestering eIF4E through mammalian target of rapamycin (mTOR)-dependent mechanisms. Although the internal ribosome entry site is an alternative translation initiation mechanism, this pathway alone cannot account for the translational capacity of hypoxic cells. This raises a fundamental question in biology as to how proteins are synthesized in periods of oxygen scarcity and eIF4E inhibition. Here we describe an oxygen-regulated translation initiation complex that mediates selective cap-dependent protein synthesis. We show that hypoxia stimulates the formation of a complex that includes the oxygen-regulated hypoxia-inducible factor 2alpha (HIF-2alpha), the RNA-binding protein RBM4 and the cap-binding eIF4E2, an eIF4E homologue. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) analysis identified an RNA hypoxia response element (rHRE) that recruits this complex to a wide array of mRNAs, including that encoding the epidermal growth factor receptor. Once assembled at the rHRE, the HIF-2alpha-RBM4-eIF4E2 complex captures the 5' cap and targets mRNAs to polysomes for active translation, thereby evading hypoxia-induced repression of protein synthesis. These findings demonstrate that cells have evolved a program by which oxygen tension switches the basic translation initiation machinery.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Uniacke, James -- Holterman, Chet E -- Lachance, Gabriel -- Franovic, Aleksandra -- Jacob, Mathieu D -- Fabian, Marc R -- Payette, Josianne -- Holcik, Martin -- Pause, Arnim -- Lee, Stephen -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2012 May 6;486(7401):126-9. doi: 10.1038/nature11055.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22678294" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions/genetics ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Cell Hypoxia/physiology ; Cell Line ; Cell Line, Tumor ; Eukaryotic Initiation Factor-4E/metabolism ; Humans ; Hypoxia-Inducible Factor 1/metabolism ; Oxygen/*metabolism/pharmacology ; *Peptide Chain Initiation, Translational/drug effects ; Polyribosomes/genetics/metabolism ; RNA Cap-Binding Proteins/metabolism ; RNA Caps/genetics/metabolism ; RNA-Binding Proteins/metabolism ; Receptor, Epidermal Growth Factor/biosynthesis/genetics
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2013-06-04
    Description: DNA damage activates a signalling network that blocks cell-cycle progression, recruits DNA repair factors and/or triggers senescence or programmed cell death. Alterations in chromatin structure are implicated in the initiation and propagation of the DNA damage response. Here we further investigate the role of chromatin structure in the DNA damage response by monitoring ionizing-radiation-induced signalling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. We discover that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DNA damage response signalling by recruiting the condensin II chromatin remodelling complex to acetylated histones through bromodomain interactions. Loss of this isoform results in relaxed chromatin structure, rapid cell-cycle checkpoint recovery and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signalling and enhanced radiation-induced lethality. These data implicate Brd4, previously known for its role in transcriptional control, as an insulator of chromatin that can modulate the signalling response to DNA damage.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683358/" 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/PMC3683358/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Floyd, Scott R -- Pacold, Michael E -- Huang, Qiuying -- Clarke, Scott M -- Lam, Fred C -- Cannell, Ian G -- Bryson, Bryan D -- Rameseder, Jonathan -- Lee, Michael J -- Blake, Emily J -- Fydrych, Anna -- Ho, Richard -- Greenberger, Benjamin A -- Chen, Grace C -- Maffa, Amanda -- Del Rosario, Amanda M -- Root, David E -- Carpenter, Anne E -- Hahn, William C -- Sabatini, David M -- Chen, Clark C -- White, Forest M -- Bradner, James E -- Yaffe, Michael B -- 1-U54-CA112967-04/CA/NCI NIH HHS/ -- ES-002109/ES/NIEHS NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- P30 ES002109/ES/NIEHS NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- R01 ES015339/ES/NIEHS NIH HHS/ -- R01-ES15339/ES/NIEHS NIH HHS/ -- R21 CA109661/CA/NCI NIH HHS/ -- R21 NS063917/NS/NINDS NIH HHS/ -- R21-NS063917/NS/NINDS NIH HHS/ -- U54 CA112967/CA/NCI NIH HHS/ -- England -- Nature. 2013 Jun 13;498(7453):246-50. doi: 10.1038/nature12147. Epub 2013 Jun 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23728299" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Adenosine Triphosphatases/metabolism ; Cell Cycle Checkpoints/radiation effects ; Cell Line, Tumor ; Cell Survival/radiation effects ; Chromatin/chemistry/*metabolism/radiation effects ; *Chromatin Assembly and Disassembly/radiation effects ; *DNA Damage ; DNA Repair/radiation effects ; DNA-Binding Proteins/metabolism ; Histones/chemistry/metabolism ; Humans ; Lysine/chemistry/metabolism ; Multiprotein Complexes/metabolism ; Nuclear Proteins/chemistry/deficiency/genetics/*metabolism ; Phosphorylation/radiation effects ; Positive Transcriptional Elongation Factor B/metabolism ; Protein Isoforms/metabolism ; Radiation, Ionizing ; *Signal Transduction/radiation effects ; Transcription Factors/chemistry/deficiency/genetics/*metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2014-11-20
    Description: TP53 is commonly altered in human cancer, and Tp53 reactivation suppresses tumours in vivo in mice (TP53 and Tp53 are also known as p53). This strategy has proven difficult to implement therapeutically, and here we examine an alternative strategy by manipulating the p53 family members, Tp63 and Tp73 (also known as p63 and p73, respectively). The acidic transactivation-domain-bearing (TA) isoforms of p63 and p73 structurally and functionally resemble p53, whereas the DeltaN isoforms (lacking the acidic transactivation domain) of p63 and p73 are frequently overexpressed in cancer and act primarily in a dominant-negative fashion against p53, TAp63 and TAp73 to inhibit their tumour-suppressive functions. The p53 family interacts extensively in cellular processes that promote tumour suppression, such as apoptosis and autophagy, thus a clear understanding of this interplay in cancer is needed to treat tumours with alterations in the p53 pathway. Here we show that deletion of the DeltaN isoforms of p63 or p73 leads to metabolic reprogramming and regression of p53-deficient tumours through upregulation of IAPP, the gene that encodes amylin, a 37-amino-acid peptide co-secreted with insulin by the beta cells of the pancreas. We found that IAPP is causally involved in this tumour regression and that amylin functions through the calcitonin receptor (CalcR) and receptor activity modifying protein 3 (RAMP3) to inhibit glycolysis and induce reactive oxygen species and apoptosis. Pramlintide, a synthetic analogue of amylin that is currently used to treat type 1 and type 2 diabetes, caused rapid tumour regression in p53-deficient thymic lymphomas, representing a novel strategy to target p53-deficient cancers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312210/" 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/PMC4312210/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Venkatanarayan, Avinashnarayan -- Raulji, Payal -- Norton, William -- Chakravarti, Deepavali -- Coarfa, Cristian -- Su, Xiaohua -- Sandur, Santosh K -- Ramirez, Marc S -- Lee, Jaehuk -- Kingsley, Charles V -- Sananikone, Eliot F -- Rajapakshe, Kimal -- Naff, Katherine -- Parker-Thornburg, Jan -- Bankson, James A -- Tsai, Kenneth Y -- Gunaratne, Preethi H -- Flores, Elsa R -- CA-16672/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P50CA136411/CA/NCI NIH HHS/ -- R01 CA134796/CA/NCI NIH HHS/ -- R01 CA160394/CA/NCI NIH HHS/ -- R01CA134796/CA/NCI NIH HHS/ -- R01CA160394/CA/NCI NIH HHS/ -- England -- Nature. 2015 Jan 29;517(7536):626-30. doi: 10.1038/nature13910. Epub 2014 Nov 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [3] Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [4] Metastasis Research Center, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. ; 1] Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. ; Department of Veterinary Medicine and Surgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. ; Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, USA. ; 1] Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [3] Metastasis Research Center, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. ; 1] Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [3] Metastasis Research Center, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [4] Radiation Biology &Health Sciences Division, Bhabha Atomic Research Center, Mumbai 400085, India. ; Department of Imaging Physics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. ; Department of Genetics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. ; 1] Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Department of Dermatology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. ; Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409149" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics/pathology ; DNA-Binding Proteins/genetics/metabolism ; Female ; Genes, Tumor Suppressor ; Humans ; Islet Amyloid Polypeptide/*metabolism/pharmacology/secretion/therapeutic use ; Lymphoma/drug therapy/genetics/*metabolism/*pathology ; Male ; Mice ; Nuclear Proteins/genetics/metabolism ; Phosphoproteins/genetics/metabolism ; Receptor Activity-Modifying Protein 3/metabolism ; Receptors, Calcitonin/metabolism ; Thymus Gland/metabolism/pathology ; Trans-Activators/genetics/metabolism ; Tumor Suppressor Protein p53/*deficiency/genetics ; Tumor Suppressor Proteins/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2014-07-22
    Description: Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is characterized by elevated glycogen levels and fat deposition. These consistent metabolic alterations are associated with normoxic stabilization of hypoxia-inducible factors (HIFs) secondary to von Hippel-Lindau (VHL) mutations that occur in over 90% of ccRCC tumours. However, kidney-specific VHL deletion in mice fails to elicit ccRCC-specific metabolic phenotypes and tumour formation, suggesting that additional mechanisms are essential. Recent large-scale sequencing analyses revealed the loss of several chromatin remodelling enzymes in a subset of ccRCC (these included polybromo-1, SET domain containing 2 and BRCA1-associated protein-1, among others), indicating that epigenetic perturbations are probably important contributors to the natural history of this disease. Here we used an integrative approach comprising pan-metabolomic profiling and metabolic gene set analysis and determined that the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) is uniformly depleted in over six hundred ccRCC tumours examined. Notably, the human FBP1 locus resides on chromosome 9q22, the loss of which is associated with poor prognosis for ccRCC patients. Our data further indicate that FBP1 inhibits ccRCC progression through two distinct mechanisms. First, FBP1 antagonizes glycolytic flux in renal tubular epithelial cells, the presumptive ccRCC cell of origin, thereby inhibiting a potential Warburg effect. Second, in pVHL (the protein encoded by the VHL gene)-deficient ccRCC cells, FBP1 restrains cell proliferation, glycolysis and the pentose phosphate pathway in a catalytic-activity-independent manner, by inhibiting nuclear HIF function via direct interaction with the HIF inhibitory domain. This unique dual function of the FBP1 protein explains its ubiquitous loss in ccRCC, distinguishing FBP1 from previously identified tumour suppressors that are not consistently mutated in all tumours.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162811/" 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/PMC4162811/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Bo -- Qiu, Bo -- Lee, David S M -- Walton, Zandra E -- Ochocki, Joshua D -- Mathew, Lijoy K -- Mancuso, Anthony -- Gade, Terence P F -- Keith, Brian -- Nissim, Itzhak -- Simon, M Celeste -- CA104838/CA/NCI NIH HHS/ -- DK053761/DK/NIDDK NIH HHS/ -- F30 CA177106/CA/NCI NIH HHS/ -- F32 CA192758/CA/NCI NIH HHS/ -- P01 CA104838/CA/NCI NIH HHS/ -- P30 CA016520/CA/NCI NIH HHS/ -- R01 DK053761/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Sep 11;513(7517):251-5. doi: 10.1038/nature13557. Epub 2014 Jul 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Howard Hughes Medical Institute, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Pediatrics, Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Division of Child Development and Metabolic Disease, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Howard Hughes Medical Institute, Philadelphia, Pennsylvania 19104, USA [3] Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043030" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Carcinoma, Renal Cell/*enzymology/genetics/physiopathology ; Cell Line ; Cell Line, Tumor ; Cell Proliferation ; Disease Progression ; Epithelial Cells/metabolism ; Fructose-Bisphosphatase/chemistry/genetics/*metabolism ; Glycolysis ; Humans ; Kidney Neoplasms/*enzymology/genetics/physiopathology ; Models, Molecular ; NADP/metabolism ; Protein Structure, Tertiary ; Swine
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2015-09-15
    Description: Bromodomain and extra terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic opportunity by directly targeting bromodomain proteins that bind acetylated chromatin marks. Early clinical trials have shown promise, especially in acute myeloid leukaemia, and therefore the evaluation of resistance mechanisms is crucial to optimize the clinical efficacy of these drugs. Here we use primary mouse haematopoietic stem and progenitor cells immortalized with the fusion protein MLL-AF9 to generate several single-cell clones that demonstrate resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is not mediated through increased drug efflux or metabolism, but is shown to emerge from leukaemia stem cells both ex vivo and in vivo. Chromatin-bound BRD4 is globally reduced in resistant cells, whereas the expression of key target genes such as Myc remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors, in human and mouse leukaemia cells, is in part a consequence of increased Wnt/beta-catenin signalling, and negative regulation of this pathway results in restoration of sensitivity to I-BET in vitro and in vivo. Together, these findings provide new insights into the biology of acute myeloid leukaemia, highlight potential therapeutic limitations of BET inhibitors, and identify strategies that may enhance the clinical utility of these unique targeted therapies.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fong, Chun Yew -- Gilan, Omer -- Lam, Enid Y N -- Rubin, Alan F -- Ftouni, Sarah -- Tyler, Dean -- Stanley, Kym -- Sinha, Devbarna -- Yeh, Paul -- Morison, Jessica -- Giotopoulos, George -- Lugo, Dave -- Jeffrey, Philip -- Lee, Stanley Chun-Wei -- Carpenter, Christopher -- Gregory, Richard -- Ramsay, Robert G -- Lane, Steven W -- Abdel-Wahab, Omar -- Kouzarides, Tony -- Johnstone, Ricky W -- Dawson, Sarah-Jane -- Huntly, Brian J P -- Prinjha, Rab K -- Papenfuss, Anthony T -- Dawson, Mark A -- England -- Nature. 2015 Sep 24;525(7570):538-42. doi: 10.1038/nature14888. Epub 2015 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. ; Sir Peter MacCallum Department of Oncology, The University of Melbourne, East Melbourne, Victoria 3002, Australia. ; Department of Haematology, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. ; Bioinformatics Division, The Walter &Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia. ; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia. ; Department of Haematology, Cambridge Institute for Medical Research and Wellcome Trust-MRC Stem Cell Institute, Cambridge CB2 0XY, UK. ; Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK. ; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA. ; QIMR Berghofer Medical Research Institute, University of Queensland, Brisbane, Queensland 4029, Australia. ; Gurdon Institute and Department of Pathology, Tennis Court Road, Cambridge CB2 1QN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26367796" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Azepines/pharmacology ; Benzodiazepines/*pharmacology ; Cell Line, Tumor ; Cells, Cultured ; Chromatin/metabolism ; Clone Cells/drug effects/metabolism/pathology ; Drug Resistance, Neoplasm/*drug effects/genetics ; Epigenesis, Genetic ; Gene Expression Regulation, Neoplastic/drug effects ; Genes, myc/genetics ; Hematopoietic Stem Cells/cytology/drug effects/metabolism ; Humans ; Leukemia, Myeloid, Acute/*drug therapy/genetics/*metabolism/pathology ; Mice ; Molecular Targeted Therapy ; Neoplastic Stem Cells/*drug effects/metabolism/*pathology ; Nuclear Proteins/*antagonists & inhibitors/metabolism ; Transcription Factors/*antagonists & inhibitors/metabolism ; Transcription, Genetic/drug effects ; Triazoles/pharmacology ; Wnt Signaling Pathway/drug effects ; beta Catenin/metabolism
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2011-10-04
    Description: Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC and the polymerase-associated factor complex (PAFc), are associated with the BET family of acetyl-lysine recognizing, chromatin 'adaptor' proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL-AF9 and human MLL-AF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679520/" 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/PMC3679520/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dawson, Mark A -- Prinjha, Rab K -- Dittmann, Antje -- Giotopoulos, George -- Bantscheff, Marcus -- Chan, Wai-In -- Robson, Samuel C -- Chung, Chun-wa -- Hopf, Carsten -- Savitski, Mikhail M -- Huthmacher, Carola -- Gudgin, Emma -- Lugo, Dave -- Beinke, Soren -- Chapman, Trevor D -- Roberts, Emma J -- Soden, Peter E -- Auger, Kurt R -- Mirguet, Olivier -- Doehner, Konstanze -- Delwel, Ruud -- Burnett, Alan K -- Jeffrey, Phillip -- Drewes, Gerard -- Lee, Kevin -- Huntly, Brian J P -- Kouzarides, Tony -- 092096/Wellcome Trust/United Kingdom -- G0800784/Medical Research Council/United Kingdom -- G116/187/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2011 Oct 2;478(7370):529-33. doi: 10.1038/nature10509.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge CB2 0XY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21964340" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; Chromatin/genetics/*metabolism ; Chromatin Immunoprecipitation ; Disease Models, Animal ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/drug effects ; Heterocyclic Compounds with 4 or More Rings/pharmacology/therapeutic use ; Humans ; Leukemia, Myeloid, Acute/*drug therapy/genetics/*metabolism/pathology ; Mice ; Models, Molecular ; Multiprotein Complexes/chemistry/metabolism ; Myeloid-Lymphoid Leukemia Protein/*metabolism ; Oncogene Proteins, Fusion/*metabolism ; Protein Binding/drug effects ; Proteomics ; Transcription Factors/*antagonists & inhibitors/*metabolism ; Transcription, Genetic/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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