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  1. Article ; Online: Corrigendium: Effects of RAS on the genesis of embryonal rhabdomyosarcoma.

    Langenau, David M / Keefe, Matthew D / Storer, Narie Y / Guyon, Jeffrey R / Kutok, Jeffery L / Le, Xiuning / Goessling, Wolfram / Neuberg, Donna S / Kunkel, Louis M / Zon, Leonard I

    Genes & development

    2024  Volume 38, Issue 5-6, Page(s) 289

    Language English
    Publishing date 2024-04-15
    Publishing country United States
    Document type Journal Article ; Published Erratum
    ZDB-ID 806684-x
    ISSN 1549-5477 ; 0890-9369
    ISSN (online) 1549-5477
    ISSN 0890-9369
    DOI 10.1101/gad.351747.124
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Zebrafish models of p53 functions.

    Storer, Narie Y / Zon, Leonard I

    Cold Spring Harbor perspectives in biology

    2010  Volume 2, Issue 8, Page(s) a001123

    Abstract: Zebrafish models have significantly contributed to our understanding of vertebrate development and, more recently, human disease. The growing number of genetic tools available in zebrafish research has resulted in the identification of many genes ... ...

    Abstract Zebrafish models have significantly contributed to our understanding of vertebrate development and, more recently, human disease. The growing number of genetic tools available in zebrafish research has resulted in the identification of many genes involved in developmental and disease processes. In particular, studies in the zebrafish have clarified roles of the p53 tumor suppressor in the formation of specific tumor types, as well as roles of p53 family members during embryonic development. The zebrafish has also been instrumental in identifying novel mechanisms of p53 regulation and highlighting the importance of these mechanisms in vivo. This article will summarize how zebrafish models have been used to reveal numerous, important aspects of p53 function.
    MeSH term(s) Animals ; Apoptosis ; Cell Cycle ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation ; Gene Expression Regulation, Neoplastic ; Genes, p53 ; Humans ; Models, Animal ; Models, Genetic ; Molecular Biology/methods ; Nuclear Proteins/metabolism ; Phosphoproteins ; Ribosomal Proteins/metabolism ; Trans-Activators ; Tumor Protein p73 ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Proteins/metabolism ; Zebrafish ; Zebrafish Proteins
    Chemical Substances DNA-Binding Proteins ; Nuclear Proteins ; Phosphoproteins ; Ribosomal Proteins ; Tp63 protein, zebrafish ; Trans-Activators ; Tumor Protein p73 ; Tumor Suppressor Protein p53 ; Tumor Suppressor Proteins ; Zebrafish Proteins
    Language English
    Publishing date 2010-05-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ISSN 1943-0264
    ISSN (online) 1943-0264
    DOI 10.1101/cshperspect.a001123
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The histone methyltransferase SUV39H1 suppresses embryonal rhabdomyosarcoma formation in zebrafish.

    Albacker, Colleen E / Storer, Narie Y / Langdon, Erin M / Dibiase, Anthony / Zhou, Yi / Langenau, David M / Zon, Leonard I

    PloS one

    2013  Volume 8, Issue 5, Page(s) e64969

    Abstract: Epigenetics, or the reversible and heritable marks of gene regulation not including DNA sequence, encompasses chromatin modifications on both the DNA and histones and is as important as the DNA sequence itself. Chromatin-modifying factors are playing an ... ...

    Abstract Epigenetics, or the reversible and heritable marks of gene regulation not including DNA sequence, encompasses chromatin modifications on both the DNA and histones and is as important as the DNA sequence itself. Chromatin-modifying factors are playing an increasingly important role in tumorigenesis, particularly among pediatric rhabdomyosarcomas (RMS), revealing potential novel therapeutic targets. We performed an overexpression screen of chromatin-modifying factors in a KRAS(G12D)-driven zebrafish model for RMS. Here, we describe the identification of a histone H3 lysine 9 histone methyltransferase, SUV39H1, as a suppressor of embryonal RMS formation in zebrafish. This suppression is specific to the histone methyltransferase activity of SUV39H1, as point mutations in the SET domain lacked the effect. SUV39H1-overexpressing and control tumors have a similar proliferation rate, muscle differentiation state, and tumor growth rate. Strikingly, SUV39H1-overexpressing fish initiate fewer tumors, which results in the observed suppressive phenotype. We demonstrate that the delayed tumor onset occurs between 5 and 7 days post fertilization. Gene expression profiling at these stages revealed that in the context of KRAS(G12D) overexpression, SUV39H1 may suppress cell cycle progression. Our studies provide evidence for the role of SUV39H1 as a tumor suppressor.
    MeSH term(s) Animals ; Carcinogenesis/genetics ; Carcinogenesis/pathology ; Cell Cycle/genetics ; Cell Differentiation/genetics ; Cell Proliferation ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Genes, Suppressor ; Humans ; Methyltransferases/chemistry ; Methyltransferases/genetics ; Methyltransferases/metabolism ; Muscles/enzymology ; Muscles/pathology ; Protein Structure, Tertiary ; Rhabdomyosarcoma, Embryonal/enzymology ; Rhabdomyosarcoma, Embryonal/genetics ; Rhabdomyosarcoma, Embryonal/pathology ; Zebrafish ; Zebrafish Proteins/chemistry ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism
    Chemical Substances Zebrafish Proteins ; Methyltransferases (EC 2.1.1.-) ; suv39h1a protein, zebrafish (EC 2.1.1.-)
    Language English
    Publishing date 2013-05-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0064969
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Zebrafish rhabdomyosarcoma reflects the developmental stage of oncogene expression during myogenesis.

    Storer, Narie Y / White, Richard M / Uong, Audrey / Price, Emily / Nielsen, G Petur / Langenau, David M / Zon, Leonard I

    Development (Cambridge, England)

    2013  Volume 140, Issue 14, Page(s) 3040–3050

    Abstract: Rhabdomyosarcoma is a pediatric malignancy thought to arise from the uncontrolled proliferation of myogenic cells. Here, we have generated models of rhabdomyosarcoma in the zebrafish by inducing oncogenic KRAS(G12D) expression at different stages during ... ...

    Abstract Rhabdomyosarcoma is a pediatric malignancy thought to arise from the uncontrolled proliferation of myogenic cells. Here, we have generated models of rhabdomyosarcoma in the zebrafish by inducing oncogenic KRAS(G12D) expression at different stages during muscle development. Several zebrafish promoters were used, including the cdh15 and rag2 promoters, which drive gene expression in early muscle progenitors, and the mylz2 promoter, which is expressed in differentiating myoblasts. The tumors that developed differed in their ability to recapitulate normal myogenesis. cdh15:KRAS(G12D) and rag2:KRAS(G12D) fish developed tumors that displayed an inability to complete muscle differentiation as determined by histological appearance and gene expression analyses. By contrast, mylz2:KRAS(G12D) tumors more closely resembled mature skeletal muscle and were most similar to well-differentiated human rhabdomyosarcoma in terms of gene expression. mylz2:KRAS(G12D) fish showed significantly improved survival compared with cdh15:KRAS(G12D) and rag2:KRAS(G12D) fish. Tumor-propagating activity was enriched in myf5-expressing cell populations within all of the tumor types. Our results demonstrate that oncogenic KRAS(G12D) expression at different stages during muscle development has profound effects on the ability of tumor cells to recapitulate normal myogenesis, altering the tumorigenic capability of these cells.
    MeSH term(s) Animals ; Animals, Genetically Modified ; Cadherins/genetics ; Cardiac Myosins/genetics ; DNA-Binding Proteins/genetics ; Disease Models, Animal ; Gene Expression Regulation, Neoplastic ; Humans ; Muscle Development ; Myosin Light Chains/genetics ; Promoter Regions, Genetic ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins p21(ras) ; Rhabdomyosarcoma/genetics ; Stem Cells/metabolism ; Zebrafish/embryology ; Zebrafish/genetics ; Zebrafish/metabolism ; Zebrafish Proteins/genetics ; ras Proteins/genetics
    Chemical Substances Cadherins ; DNA-Binding Proteins ; KRAS protein, human ; Myosin Light Chains ; Proto-Oncogene Proteins ; RAG2 protein, zebrafish ; Zebrafish Proteins ; cadherin 15, zebrafish ; myosin light chain 2 ; Cardiac Myosins (EC 3.6.1.-) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; ras Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2013-07-03
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 90607-4
    ISSN 1477-9129 ; 0950-1991
    ISSN (online) 1477-9129
    ISSN 0950-1991
    DOI 10.1242/dev.087858
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  5. Article ; Online: A novel chemical screening strategy in zebrafish identifies common pathways in embryogenesis and rhabdomyosarcoma development.

    Le, Xiuning / Pugach, Emily K / Hettmer, Simone / Storer, Narie Y / Liu, Jianing / Wills, Airon A / DiBiase, Antony / Chen, Eleanor Y / Ignatius, Myron S / Poss, Kenneth D / Wagers, Amy J / Langenau, David M / Zon, Leonard I

    Development (Cambridge, England)

    2013  Volume 140, Issue 11, Page(s) 2354–2364

    Abstract: The zebrafish is a powerful genetic model that has only recently been used to dissect developmental pathways involved in oncogenesis. We hypothesized that operative pathways during embryogenesis would also be used for oncogenesis. In an effort to define ... ...

    Abstract The zebrafish is a powerful genetic model that has only recently been used to dissect developmental pathways involved in oncogenesis. We hypothesized that operative pathways during embryogenesis would also be used for oncogenesis. In an effort to define RAS target genes during embryogenesis, gene expression was evaluated in Tg(hsp70-HRAS(G12V)) zebrafish embryos subjected to heat shock. dusp6 was activated by RAS, and this was used as the basis for a chemical genetic screen to identify small molecules that interfere with RAS signaling during embryogenesis. A KRAS(G12D)-induced zebrafish embryonal rhabdomyosarcoma was then used to assess the therapeutic effects of the small molecules. Two of these inhibitors, PD98059 and TPCK, had anti-tumor activity as single agents in both zebrafish embryonal rhabdomyosarcoma and a human cell line of rhabdomyosarcoma that harbored activated mutations in NRAS. PD98059 inhibited MEK1 whereas TPCK suppressed S6K1 activity; however, the combined treatment completely suppressed eIF4B phosphorylation and decreased translation initiation. Our work demonstrates that the activated pathways in RAS induction during embryogenesis are also important in oncogenesis and that inhibition of these pathways suppresses tumor growth.
    MeSH term(s) Animals ; Animals, Genetically Modified ; Cell Line, Tumor ; Eukaryotic Initiation Factors/metabolism ; Flavonoids/pharmacology ; Gene Expression Regulation, Developmental ; Gene Expression Regulation, Neoplastic ; Humans ; MAP Kinase Kinase 1/metabolism ; Oligonucleotide Array Sequence Analysis ; Protein Biosynthesis ; Rhabdomyosarcoma/genetics ; Rhabdomyosarcoma/metabolism ; Rhabdomyosarcoma/pathology ; Ribosomal Protein S6 Kinases/metabolism ; Signal Transduction ; Tosylphenylalanyl Chloromethyl Ketone/pharmacology ; Transgenes ; Zebrafish/embryology ; Zebrafish/genetics ; Zebrafish Proteins/metabolism ; ras Proteins/metabolism
    Chemical Substances Eukaryotic Initiation Factors ; Flavonoids ; Zebrafish Proteins ; eIF-4B ; Tosylphenylalanyl Chloromethyl Ketone (402-71-1) ; Ribosomal Protein S6 Kinases (EC 2.7.11.1) ; MAP Kinase Kinase 1 (EC 2.7.12.2) ; ras Proteins (EC 3.6.5.2) ; 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (SJE1IO5E3I)
    Language English
    Publishing date 2013-04-24
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 90607-4
    ISSN 1477-9129 ; 0950-1991
    ISSN (online) 1477-9129
    ISSN 0950-1991
    DOI 10.1242/dev.088427
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  6. Article ; Online: High-throughput cell transplantation establishes that tumor-initiating cells are abundant in zebrafish T-cell acute lymphoblastic leukemia.

    Smith, Alexandra C H / Raimondi, Aubrey R / Salthouse, Chris D / Ignatius, Myron S / Blackburn, Jessica S / Mizgirev, Igor V / Storer, Narie Y / de Jong, Jill L O / Chen, Aye T / Zhou, Yi / Revskoy, Sergei / Zon, Leonard I / Langenau, David M

    Blood

    2010  Volume 115, Issue 16, Page(s) 3296–3303

    Abstract: Self-renewal is a feature of cancer and can be assessed by cell transplantation into immune-compromised or immune-matched animals. However, studies in zebrafish have been severely limited by lack of these reagents. Here, Myc-induced T-cell acute ... ...

    Abstract Self-renewal is a feature of cancer and can be assessed by cell transplantation into immune-compromised or immune-matched animals. However, studies in zebrafish have been severely limited by lack of these reagents. Here, Myc-induced T-cell acute lymphoblastic leukemias (T-ALLs) have been made in syngeneic, clonal zebrafish and can be transplanted into sibling animals without the need for immune suppression. These studies show that self-renewing cells are abundant in T-ALL and comprise 0.1% to 15.9% of the T-ALL mass. Large-scale single-cell transplantation experiments established that T-ALLs can be initiated from a single cell and that leukemias exhibit wide differences in tumor-initiating potential. T-ALLs also can be introduced into clonal-outcrossed animals, and T-ALLs arising in mixed genetic backgrounds can be transplanted into clonal recipients without the need for major histocompatibility complex matching. Finally, high-throughput imaging methods are described that allow large numbers of fluorescent transgenic animals to be imaged simultaneously, facilitating the rapid screening of engrafted animals. Our experiments highlight the large numbers of zebrafish that can be experimentally assessed by cell transplantation and establish new high-throughput methods to functionally interrogate gene pathways involved in cancer self-renewal.
    MeSH term(s) Animals ; Animals, Genetically Modified ; Cell Separation ; Disease Models, Animal ; Flow Cytometry ; Image Processing, Computer-Assisted ; Microscopy, Fluorescence ; Neoplasm Transplantation/methods ; Neoplastic Stem Cells/pathology ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology ; Zebrafish/genetics
    Language English
    Publishing date 2010-01-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood-2009-10-246488
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  7. Article: Effects of RAS on the genesis of embryonal rhabdomyosarcoma.

    Langenau, David M / Keefe, Matthew D / Storer, Narie Y / Guyon, Jeffrey R / Kutok, Jeffery L / Le, Xiuning / Goessling, Wolfram / Neuberg, Donna S / Kunkel, Louis M / Zon, Leonard I

    Genes & development

    2007  Volume 21, Issue 11, Page(s) 1382–1395

    Abstract: Embryonal rhabdomyosarcoma (ERMS) is a devastating cancer with specific features of muscle differentiation that can result from mutational activation of RAS family members. However, to date, RAS pathway activation has not been reported in a majority of ... ...

    Abstract Embryonal rhabdomyosarcoma (ERMS) is a devastating cancer with specific features of muscle differentiation that can result from mutational activation of RAS family members. However, to date, RAS pathway activation has not been reported in a majority of ERMS patients. Here, we have created a zebrafish model of RAS-induced ERMS, in which animals develop externally visible tumors by 10 d of life. Microarray analysis and cross-species comparisons identified two conserved gene signatures found in both zebrafish and human ERMS, one associated with tumor-specific and tissue-restricted gene expression in rhabdomyosarcoma and a second comprising a novel RAS-induced gene signature. Remarkably, our analysis uncovered that RAS pathway activation is exceedingly common in human RMS. We also created a new transgenic coinjection methodology to fluorescently label distinct subpopulations of tumor cells based on muscle differentiation status. In conjunction with fluorescent activated cell sorting, cell transplantation, and limiting dilution analysis, we were able to identify the cancer stem cell in zebrafish ERMS. When coupled with gene expression studies of this cell population, we propose that the zebrafish RMS cancer stem cell shares similar self-renewal programs as those found in activated satellite cells.
    MeSH term(s) Adenosine Deaminase/genetics ; Animals ; Animals, Genetically Modified ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Cell Differentiation ; Cell Transformation, Neoplastic ; Cells, Cultured ; DNA-Binding Proteins/genetics ; Embryo, Nonmammalian/cytology ; Embryo, Nonmammalian/metabolism ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Genes, ras/physiology ; Humans ; In Situ Hybridization ; Kidney/cytology ; Kidney/metabolism ; Kidney/pathology ; Microinjections ; Muscle, Skeletal/cytology ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/pathology ; Oligonucleotide Array Sequence Analysis ; RNA-Binding Proteins ; Rhabdomyosarcoma, Embryonal/etiology ; Rhabdomyosarcoma, Embryonal/genetics ; Rhabdomyosarcoma, Embryonal/pathology ; Zebrafish/genetics ; Zebrafish/metabolism
    Chemical Substances Biomarkers, Tumor ; DNA-Binding Proteins ; RNA-Binding Proteins ; Rag2 protein, mouse ; ADARB1 protein, human (EC 3.5.4.4) ; Adenosine Deaminase (EC 3.5.4.4)
    Language English
    Publishing date 2007-05-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 806684-x
    ISSN 1549-5477 ; 0890-9369
    ISSN (online) 1549-5477
    ISSN 0890-9369
    DOI 10.1101/gad.1545007
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