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    Nature genetics. 2015 Jul 27. pii: ng.3362. doi: 10.1038/ng.3362
    Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options.
    Fischer U1,  Forster M2,  Rinaldi A3,  Risch T4,  Sungalee S5,  Warnatz HJ6,  Bornhauser B7,  Gombert M8,  Kratsch C9,  Stütz AM10,  Sultan M11,  Tchinda J12,  Worth CL13,  Amstislavskiy V14,  Badarinarayan N15,  Baruchel A16,  Bartram T17,  Basso G18,  Canpolat C19,  Cario G20,  Cavé H21,  Dakaj D22,  Delorenzi M23,  Dobay MP24,  Eckert C25,  Ellinghaus E26,  Eugster S27,  Frismantas V28,  Ginzel S29,  Haas OA30,  Heidenreich O31,  Hemmrich-Stanisak G32,  Hezaveh K33,  Höll JI34,  Hornhardt S35,  Husemann P36,  Kachroo P37,  Kratz CP38,  Kronnie GT39,  Marovca B40,  Niggli F41,  McHardy AC42,  Moorman AV43,  Panzer-Grümayer R44,  Petersen BS45,  Raeder B46,  Ralser M47,  Rosenstiel P48,  Schäfer D49,  Schrappe M50,  Schreiber S51,  Schütte M52,  Stade B53,  Thiele R54,  Weid NV55,  Vora A56,  Zaliova M57,  Zhang L58,  Zichner T59,  Zimmermann M60,  Lehrach H61,  Borkhardt A62,  Bourquin JP63,  Franke A64,  Korbel JO65,  Stanulla M66,  Yaspo ML67
    Author information
    1Clinic for Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
    2Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    3Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
    4Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
    5European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
    6Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
    7Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
    8Clinic for Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
    9Department of Algorithmic Bioinformatics, Heinrich Heine University, Düsseldorf, Germany.
    10European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
    11Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
    12Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
    13Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
    14Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
    15Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    16Department of Pediatric Hemato-Immunology, Hôpital Robert Debré and Paris Diderot University, Paris, France.
    17Department of Pediatrics, Christian Albrechts University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
    18Department of Pediatrics, Laboratory of Pediatric Hematology/Oncology, University of Padova, Padova, Italy.
    19Department of Pediatrics, Acy`badem University Medical School, Atas¸ehir, Istanbul, Turkey.
    20Department of Pediatrics, Christian Albrechts University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
    21Department of Genetics, Hôpital Robert Debré and Paris Diderot University, Paris, France.
    22Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
    23Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland.
    24Swiss Institute for Bioinformatics (SIB), Lausanne, Switzerland.
    25Pediatric Hematology and Oncology, Charité University Hospital, Berlin, Germany.
    26Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    27Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
    28Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
    29Clinic for Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
    30Children's Cancer Research Institute, Vienna, Austria.
    31Northern Institute of Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
    32Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    33Clinic for Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
    34Clinic for Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
    35Federal Office for Radiation Protection, Oberschleissheim, Germany.
    36Clinic for Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
    37Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    38Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
    39Department of Pediatrics, Laboratory of Pediatric Hematology/Oncology, University of Padova, Padova, Italy.
    40Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
    41Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
    42Department of Algorithmic Bioinformatics, Heinrich Heine University, Düsseldorf, Germany.
    43Northern Institute of Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
    44Children's Cancer Research Institute, Vienna, Austria.
    45Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    46European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
    47Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
    48Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    49Clinic for Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
    50Department of Pediatrics, Christian Albrechts University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
    51Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    52Alacris Theranostics GmbH, Berlin, Germany.
    53Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    54Department of Computer Science, Bonn Rhine Sieg University of Applied Sciences, Sankt Augustin, Germany.
    55Universitäts-Kinderspital beider Basel (UKBB), Basel, Switzerland.
    56Sheffield Children's Hospital, Sheffield, United Kingdom.
    57Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
    58Clinic for Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
    59European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
    60Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
    61Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
    62Clinic for Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
    63Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
    64Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
    65European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
    66Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
    67Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
    Abstract

    TCF3-HLF-positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. We identified recurrent intragenic deletions of PAX5 or VPREB1 in constellation with the fusion of TCF3 and HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin toward a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics but sensitivity to glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease.


    Publikations ID: 26214592
    Quelle: öffnen
     
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