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  • 1
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    Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-08-19
    Description: T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy with a dismal overall prognosis, including a relapse rate of up to 25%, mainly because of the lack of non-cytotoxic targeted therapy options. Drugs that target the function of key epigenetic factors have been approved in the context of haematopoietic disorders, and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified; however, 'epigenetic' drugs are not currently used for T-ALL treatment. Recently, we described that the polycomb repressive complex 2 (PRC2) has a tumour-suppressor role in T-ALL. Here we delineated the role of the histone 3 lysine 27 (H3K27) demethylases JMJD3 and UTX in T-ALL. We show that JMJD3 is essential for the initiation and maintenance of T-ALL, as it controls important oncogenic gene targets by modulating H3K27 methylation. By contrast, we found that UTX functions as a tumour suppressor and is frequently genetically inactivated in T-ALL. Moreover, we demonstrated that the small molecule inhibitor GSKJ4 (ref. 5) affects T-ALL growth, by targeting JMJD3 activity. These findings show that two proteins with a similar enzymatic function can have opposing roles in the context of the same disease, paving the way for treating haematopoietic malignancies with a new category of epigenetic inhibitors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209203/" 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/PMC4209203/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ntziachristos, Panagiotis -- Tsirigos, Aristotelis -- Welstead, G Grant -- Trimarchi, Thomas -- Bakogianni, Sofia -- Xu, Luyao -- Loizou, Evangelia -- Holmfeldt, Linda -- Strikoudis, Alexandros -- King, Bryan -- Mullenders, Jasper -- Becksfort, Jared -- Nedjic, Jelena -- Paietta, Elisabeth -- Tallman, Martin S -- Rowe, Jacob M -- Tonon, Giovanni -- Satoh, Takashi -- Kruidenier, Laurens -- Prinjha, Rab -- Akira, Shizuo -- Van Vlierberghe, Pieter -- Ferrando, Adolfo A -- Jaenisch, Rudolf -- Mullighan, Charles G -- Aifantis, Iannis -- 1R01CA105129/CA/NCI NIH HHS/ -- 1R01CA133379/CA/NCI NIH HHS/ -- 1R01CA149655/CA/NCI NIH HHS/ -- 5 T32 CA009161-37/CA/NCI NIH HHS/ -- 5P30CA16087-31/CA/NCI NIH HHS/ -- 5R01CA169784/CA/NCI NIH HHS/ -- 5R01CA173636/CA/NCI NIH HHS/ -- K99 CA188293/CA/NCI NIH HHS/ -- K99CA188293/CA/NCI NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- P30 CA016087/CA/NCI NIH HHS/ -- P30 CA016087-30/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- R01 CA105129/CA/NCI NIH HHS/ -- R01 CA133379/CA/NCI NIH HHS/ -- R01 CA149655/CA/NCI NIH HHS/ -- R01 CA173636/CA/NCI NIH HHS/ -- R01CA120196/CA/NCI NIH HHS/ -- R37 HD045022/HD/NICHD NIH HHS/ -- R37-HD04502/HD/NICHD NIH HHS/ -- U10 CA180820/CA/NCI NIH HHS/ -- U10 CA180827/CA/NCI NIH HHS/ -- U10 CA21115/CA/NCI NIH HHS/ -- U24 CA114737/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Oct 23;514(7523):513-7. doi: 10.1038/nature13605. Epub 2014 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [2] NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, New York 10016, USA [3]. ; 1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [2] Center for Health Informatics and Bioinformatics, NYU School of Medicine, New York, New York 10016, USA [3]. ; 1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3]. ; 1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [2] NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, New York 10016, USA. ; Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA. ; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Montefiore Medical Center North, Bronx, New York, New York 10467, USA. ; Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; 1] Technion, Israel Institute of Technology, Haifa 31096, Israel [2] Shaare Zedek Medical Center, Jerusalem 9103102, Israel. ; Functional Genomics of Cancer Unit, Division of Molecular Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, 20132 Milan, Italy. ; 1] Laboratory of Host Defense, WPI Immunology Frontier Research Center (WPI IFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan [2] Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, 3-1Yamada-oka, Suita, Osaka 565-0871, Japan. ; Epinova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Medicines Research Centre, GunnelsWood Road, Stevenage SG1 2NY, UK. ; 1] Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA [2] Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium. ; 1] Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA [2] Department of Pathology, Columbia University Medical Center, New York, New York 10032, USA [3] Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA. ; 1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA [2] Department of Biology, 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/25132549" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Benzazepines/pharmacology ; Epigenesis, Genetic/drug effects ; Histone Demethylases/genetics/*metabolism ; Histones/chemistry/metabolism ; Jumonji Domain-Containing Histone Demethylases/antagonists & ; inhibitors/*metabolism ; Lysine/metabolism ; Methylation/drug effects ; Mice ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug ; therapy/*enzymology/genetics/pathology ; Pyrimidines/pharmacology ; Tumor Suppressor Proteins/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    The genetic basis of early T-cell precursor acute lymphoblastic leukaemia (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-01-13
    Description: Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267575/" 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/PMC3267575/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Jinghui -- Ding, Li -- Holmfeldt, Linda -- Wu, Gang -- Heatley, Sue L -- Payne-Turner, Debbie -- Easton, John -- Chen, Xiang -- Wang, Jianmin -- Rusch, Michael -- Lu, Charles -- Chen, Shann-Ching -- Wei, Lei -- Collins-Underwood, J Racquel -- Ma, Jing -- Roberts, Kathryn G -- Pounds, Stanley B -- Ulyanov, Anatoly -- Becksfort, Jared -- Gupta, Pankaj -- Huether, Robert -- Kriwacki, Richard W -- Parker, Matthew -- McGoldrick, Daniel J -- Zhao, David -- Alford, Daniel -- Espy, Stephen -- Bobba, Kiran Chand -- Song, Guangchun -- Pei, Deqing -- Cheng, Cheng -- Roberts, Stefan -- Barbato, Michael I -- Campana, Dario -- Coustan-Smith, Elaine -- Shurtleff, Sheila A -- Raimondi, Susana C -- Kleppe, Maria -- Cools, Jan -- Shimano, Kristin A -- Hermiston, Michelle L -- Doulatov, Sergei -- Eppert, Kolja -- Laurenti, Elisa -- Notta, Faiyaz -- Dick, John E -- Basso, Giuseppe -- Hunger, Stephen P -- Loh, Mignon L -- Devidas, Meenakshi -- Wood, Brent -- Winter, Stuart -- Dunsmore, Kimberley P -- Fulton, Robert S -- Fulton, Lucinda L -- Hong, Xin -- Harris, Christopher C -- Dooling, David J -- Ochoa, Kerri -- Johnson, Kimberly J -- Obenauer, John C -- Evans, William E -- Pui, Ching-Hon -- Naeve, Clayton W -- Ley, Timothy J -- Mardis, Elaine R -- Wilson, Richard K -- Downing, James R -- Mullighan, Charles G -- CA114766/CA/NCI NIH HHS/ -- CA98413/CA/NCI NIH HHS/ -- CA98543/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- P30 CA021765-33/CA/NCI NIH HHS/ -- P30CA021765/CA/NCI NIH HHS/ -- U01GM92666/GM/NIGMS NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- England -- Nature. 2012 Jan 11;481(7380):157-63. doi: 10.1038/nature10725.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Computational Biology and Bioinformatics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22237106" target="_blank"〉PubMed〈/a〉
    Keywords: Age of Onset ; Child ; DNA Copy Number Variations/genetics ; Genes, ras/genetics ; Genetic Predisposition to Disease/*genetics ; Genome, Human/genetics ; Genomics ; Hematopoiesis/genetics ; Histones/metabolism ; Humans ; Janus Kinases/genetics/metabolism ; Leukemia, Myeloid, Acute/drug therapy/genetics/pathology ; Molecular Sequence Data ; Mutation/*genetics ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/*genetics/pathology ; Receptors, Interleukin-7/genetics ; Sequence Analysis, DNA ; Signal Transduction/genetics ; Stem Cells/metabolism/pathology ; T-Lymphocytes/metabolism/pathology ; Translocation, Genetic/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    CREBBP mutations in relapsed acute lymphoblastic leukaemia (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-03-11
    Description: Relapsed acute lymphoblastic leukaemia (ALL) is a leading cause of death due to disease in young people, but the biological determinants of treatment failure remain poorly understood. Recent genome-wide profiling of structural DNA alterations in ALL have identified multiple submicroscopic somatic mutations targeting key cellular pathways, and have demonstrated substantial evolution in genetic alterations from diagnosis to relapse. However, DNA sequence mutations in ALL have not been analysed in detail. To identify novel mutations in relapsed ALL, we resequenced 300 genes in matched diagnosis and relapse samples from 23 patients with ALL. This identified 52 somatic non-synonymous mutations in 32 genes, many of which were novel, including the transcriptional coactivators CREBBP and NCOR1, the transcription factors ERG, SPI1, TCF4 and TCF7L2, components of the Ras signalling pathway, histone genes, genes involved in histone modification (CREBBP and CTCF), and genes previously shown to be targets of recurring DNA copy number alteration in ALL. Analysis of an extended cohort of 71 diagnosis-relapse cases and 270 acute leukaemia cases that did not relapse found that 18.3% of relapse cases had sequence or deletion mutations of CREBBP, which encodes the transcriptional coactivator and histone acetyltransferase CREB-binding protein (CREBBP, also known as CBP). The mutations were either present at diagnosis or acquired at relapse, and resulted in truncated alleles or deleterious substitutions in conserved residues of the histone acetyltransferase domain. Functionally, the mutations impaired histone acetylation and transcriptional regulation of CREBBP targets, including glucocorticoid responsive genes. Several mutations acquired at relapse were detected in subclones at diagnosis, suggesting that the mutations may confer resistance to therapy. These results extend the landscape of genetic alterations in leukaemia, and identify mutations targeting transcriptional and epigenetic regulation as a mechanism of resistance in ALL.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076610/" 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/PMC3076610/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mullighan, Charles G -- Zhang, Jinghui -- Kasper, Lawryn H -- Lerach, Stephanie -- Payne-Turner, Debbie -- Phillips, Letha A -- Heatley, Sue L -- Holmfeldt, Linda -- Collins-Underwood, J Racquel -- Ma, Jing -- Buetow, Kenneth H -- Pui, Ching-Hon -- Baker, Sharyn D -- Brindle, Paul K -- Downing, James R -- DE018183/DE/NIDCR NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- P30 CA021765-31/CA/NCI NIH HHS/ -- R21 DE018183/DE/NIDCR NIH HHS/ -- R21 DE018183-02/DE/NIDCR NIH HHS/ -- England -- Nature. 2011 Mar 10;471(7337):235-9. doi: 10.1038/nature09727.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21390130" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; CREB-Binding Protein/chemistry/*genetics/metabolism ; Drug Resistance, Neoplasm/genetics ; Epigenesis, Genetic/genetics ; Gene Expression Regulation, Neoplastic ; Histone Acetyltransferases/genetics/metabolism ; Histones/metabolism ; Humans ; Mutation/*genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics ; Protein Structure, Tertiary/genetics ; Recurrence
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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