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  • 1
    Publication Date: 2014-05-09
    Description: PTEN encodes a lipid phosphatase that is underexpressed in many cancers owing to deletions, mutations or gene silencing. PTEN dephosphorylates phosphatidylinositol (3,4,5)-triphosphate, thereby opposing the activity of class I phosphatidylinositol 3-kinases that mediate growth- and survival-factor signalling through phosphatidylinositol 3-kinase effectors such as AKT and mTOR. To determine whether continued PTEN inactivation is required to maintain malignancy, here we generate an RNA interference-based transgenic mouse model that allows tetracycline-dependent regulation of PTEN in a time- and tissue-specific manner. Postnatal Pten knockdown in the haematopoietic compartment produced highly disseminated T-cell acute lymphoblastic leukaemia. Notably, reactivation of PTEN mainly reduced T-cell leukaemia dissemination but had little effect on tumour load in haematopoietic organs. Leukaemia infiltration into the intestine was dependent on CCR9 G-protein-coupled receptor signalling, which was amplified by PTEN loss. Our results suggest that in the absence of PTEN, G-protein-coupled receptors may have an unanticipated role in driving tumour growth and invasion in an unsupportive environment. They further reveal that the role of PTEN loss in tumour maintenance is not invariant and can be influenced by the tissue microenvironment, thereby producing a form of intratumoral heterogeneity that is independent of cancer genotype.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165899/" 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/PMC4165899/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miething, Cornelius -- Scuoppo, Claudio -- Bosbach, Benedikt -- Appelmann, Iris -- Nakitandwe, Joy -- Ma, Jing -- Wu, Gang -- Lintault, Laura -- Auer, Martina -- Premsrirut, Prem K -- Teruya-Feldstein, Julie -- Hicks, James -- Benveniste, Helene -- Speicher, Michael R -- Downing, James R -- Lowe, Scott W -- P01 CA013106/CA/NCI NIH HHS/ -- P01 CA087497/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- P30 CA045508/CA/NCI NIH HHS/ -- S10 OD016282/OD/NIH HHS/ -- U01 CA105388/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jun 19;510(7505):402-6. doi: 10.1038/nature13239. Epub 2014 May 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [3] Department of Medicine I, Medical Center - University of Freiburg, 79106 Freiburg, Germany. ; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. ; Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; 1] Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. ; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] Howard Hughes Medical Institute, New York, New York 10065, USA. ; Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria. ; Departments of Anesthesiology and Radiology, Stony Brook University, Stony Brook, New York 11794, USA. ; 1] Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [3] Howard Hughes Medical Institute, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24805236" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chemokines/metabolism ; Gene Knockdown Techniques ; Leukemia/*enzymology/genetics/*physiopathology ; Mice, Transgenic ; PTEN Phosphohydrolase/*genetics/*metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; RNA Interference ; Receptors, G-Protein-Coupled/metabolism ; Signal Transduction ; Tumor Microenvironment/*physiology
    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: 2016-03-17
    Description: Mutations disabling the TP53 tumour suppressor gene represent the most frequent events in human cancer and typically occur through a two-hit mechanism involving a missense mutation in one allele and a 'loss of heterozygosity' deletion encompassing the other. While TP53 missense mutations can also contribute gain-of-function activities that impact tumour progression, it remains unclear whether the deletion event, which frequently includes many genes, impacts tumorigenesis beyond TP53 loss alone. Here we show that somatic heterozygous deletion of mouse chromosome 11B3, a 4-megabase region syntenic to human 17p13.1, produces a greater effect on lymphoma and leukaemia development than Trp53 deletion. Mechanistically, the effect of 11B3 loss on tumorigenesis involves co-deleted genes such as Eif5a and Alox15b (also known as Alox8), the suppression of which cooperates with Trp53 loss to produce more aggressive disease. Our results imply that the selective advantage produced by human chromosome 17p deletion reflects the combined impact of TP53 loss and the reduced dosage of linked tumour suppressor genes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836395/" 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/PMC4836395/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Yu -- Chen, Chong -- Xu, Zhengmin -- Scuoppo, Claudio -- Rillahan, Cory D -- Gao, Jianjiong -- Spitzer, Barbara -- Bosbach, Benedikt -- Kastenhuber, Edward R -- Baslan, Timour -- Ackermann, Sarah -- Cheng, Lihua -- Wang, Qingguo -- Niu, Ting -- Schultz, Nikolaus -- Levine, Ross L -- Mills, Alea A -- Lowe, Scott W -- P30 CA008748/CA/NCI NIH HHS/ -- P30 CA016042/CA/NCI NIH HHS/ -- R01 CA190261/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Mar 24;531(7595):471-5. doi: 10.1038/nature17157. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Hematology and Department of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and National Collaborative Innovation Center, Chengdu 610041, China. ; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA. ; Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Human Oncology &Pathogenesis Program and Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Hematology &Research Laboratory of Hematology, West China Hospital, Sichuan University, Chengdu 610041, China. ; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. ; Howard Hughes Medical Institute, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982726" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Cell Transformation, Neoplastic/genetics ; Chromosomes, Human, Pair 17/genetics ; Chromosomes, Mammalian/genetics ; Disease Models, Animal ; Disease Progression ; Female ; Genes, p53/*genetics ; Heterozygote ; Humans ; Leukemia, Myeloid, Acute/genetics/pathology ; Lymphoma/genetics/pathology ; Male ; Mice ; Neoplasms/*genetics/*pathology ; Peptide Initiation Factors/genetics/metabolism ; RNA-Binding Proteins/genetics/metabolism ; Sequence Deletion/*genetics ; Synteny/genetics ; Tumor Suppressor Protein p53/*deficiency
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Abstract: A segmental deletion resulting in DNAJB1-PRKACA gene fusion is now recognized as the signature genetic event of fibrolamellar hepatocellular carcinoma (FL-HCC), a rare but lethal liver cancer that primarily affects adolescents and young adults. Here we implement CRISPR-Cas9 genome editing and transposon-mediated somatic gene transfer to demonstrate that expression of either the endogenous fusion protein or a chimeric cDNA leads to the formation of indolent liver tumors in mice that closely resemble human FL-HCC. Notably, overexpression of the wild-type PRKACA was unable to fully recapitulate the oncogenic activity of DNAJB1-PRKACA, implying that FL-HCC does not simply result from enhanced PRKACA expression. Tumorigenesis was significantly enhanced by genetic activation of beta-catenin, an observation supported by evidence of recurrent Wnt pathway mutations in human FL-HCC, as well as treatment with the hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which causes tissue injury, inflammation, and fibrosis. Our study validates the DNAJB1-PRKACA fusion kinase as an oncogenic driver and candidate drug target for FL-HCC, and establishes a practical model for preclinical studies to identify strategies to treat this disease.
    Type of Publication: Journal article published
    PubMed ID: 29162699
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Acta mathematica hungarica 30 (1977), S. 19-20 
    ISSN: 1588-2632
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1588-2829
    Keywords: Primary 06B10 ; Secondary 06B15, 06D10 ; Partially ordered sets ; Hilbert groupoids ; Brouwerian semilattices ; algebraic lattices ; complete lattices
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Acta mathematica hungarica 38 (1981), S. 89-104 
    ISSN: 1588-2632
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Type of Medium: Electronic Resource
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