title: Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options.
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.
authors.affiliation: Clinic for Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Fischer
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Forster
authors.affiliation: Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Rinaldi
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Risch
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Sungalee
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Warnatz
authors.affiliation: Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Bornhauser
authors.affiliation: Clinic for Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gombert
authors.affiliation: Department of Algorithmic Bioinformatics, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Kratsch
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Stütz
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Sultan
authors.affiliation: Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Joelle
authors.initials: J
authors.lastname: Tchinda
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Worth
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Vyacheslav
authors.initials: V
authors.lastname: Amstislavskiy
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Nandini
authors.initials: N
authors.lastname: Badarinarayan
authors.affiliation: Department of Pediatric Hemato-Immunology, Hôpital Robert Debré and Paris Diderot University, Paris, France.
authors.forename: André
authors.initials: A
authors.lastname: Baruchel
authors.affiliation: Department of Pediatrics, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Thies
authors.initials: T
authors.lastname: Bartram
authors.affiliation: Department of Pediatrics, Laboratory of Pediatric Hematology/Oncology, University of Padova, Padova, Italy.
authors.forename: Giuseppe
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authors.affiliation: Department of Pediatrics, Acıbadem University Medical School, Ataşehir, Istanbul, Turkey.
authors.forename: Cengiz
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authors.lastname: Canpolat
authors.affiliation: Department of Pediatrics, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Gunnar
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authors.lastname: Cario
authors.affiliation: Department of Genetics, Hôpital Robert Debré and Paris Diderot University, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Cavé
authors.affiliation: Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Dardane
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authors.lastname: Dakaj
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland.|Swiss Institute for Bioinformatics (SIB), Lausanne, Switzerland.
authors.forename: Mauro
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authors.lastname: Delorenzi
authors.affiliation: Swiss Institute for Bioinformatics (SIB), Lausanne, Switzerland.
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authors.initials: MP
authors.lastname: Dobay
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authors.lastname: Eckert
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Ellinghaus
authors.affiliation: Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Sabrina
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authors.affiliation: Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Viktoras
authors.initials: V
authors.lastname: Frismantas
authors.affiliation: Clinic for Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.|Department of Computer Science, Bonn-Rhine-Sieg University of Applied Sciences, Sankt Augustin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ginzel
authors.affiliation: Children's Cancer Research Institute, Vienna, Austria.
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authors.initials: OA
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authors.forename: Olaf
authors.initials: O
authors.lastname: Heidenreich
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Hemmrich-Stanisak
authors.affiliation: Clinic for Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Kebria
authors.initials: K
authors.lastname: Hezaveh
authors.affiliation: Clinic for Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Jessica I
authors.initials: JI
authors.lastname: Höll
authors.affiliation: Federal Office for Radiation Protection, Oberschleissheim, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hornhardt
authors.affiliation: Clinic for Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Husemann
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Priyadarshini
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authors.initials: CP
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authors.affiliation: Department of Pediatrics, Laboratory of Pediatric Hematology/Oncology, University of Padova, Padova, Italy.
authors.forename: Geertruy
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authors.affiliation: Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
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authors.affiliation: Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Felix
authors.initials: F
authors.lastname: Niggli
authors.affiliation: Department of Algorithmic Bioinformatics, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Alice C
authors.initials: AC
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authors.affiliation: Northern Institute of Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
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authors.initials: AV
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authors.affiliation: Children's Cancer Research Institute, Vienna, Austria.
authors.forename: Renate
authors.initials: R
authors.lastname: Panzer-Grümayer
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Britt S
authors.initials: BS
authors.lastname: Petersen
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Raeder
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Meryem
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authors.lastname: Ralser
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Philip
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authors.lastname: Rosenstiel
authors.affiliation: Clinic for Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
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authors.initials: D
authors.lastname: Schäfer
authors.affiliation: Department of Pediatrics, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
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authors.initials: M
authors.lastname: Schrappe
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Stefan
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authors.lastname: Schreiber
authors.affiliation: Alacris Theranostics GmbH, Berlin, Germany.
authors.forename: Moritz
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authors.lastname: Schütte
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Björn
authors.initials: B
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authors.affiliation: Department of Computer Science, Bonn-Rhine-Sieg University of Applied Sciences, Sankt Augustin, Germany.
authors.forename: Ralf
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authors.affiliation: Universitäts-Kinderspital beider Basel (UKBB), Basel, Switzerland.
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authors.initials: A
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authors.affiliation: Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.|Childhood Leukaemia Investigation Prague (CLIP), Department of Pediatric Hematology/Oncology, Second Faculty of Medicine, Charles University Prague, Prague, Czech Republic.
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authors.lastname: Zaliova
authors.affiliation: Clinic for Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.|Department of Hematology, Union Hospital, Fujian Medical University, Fuzhou, China.
authors.forename: Langhui
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authors.forename: Martin
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authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.|Alacris Theranostics GmbH, Berlin, Germany.|Dahlem Centre for Genome Reseach and Medical Systems Biology, Berlin, Germany.
authors.forename: Hans
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authors.affiliation: Clinic for Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
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authors.affiliation: Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bourquin
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Andre
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authors.lastname: Franke
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
authors.forename: Jan O
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authors.affiliation: Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Martin
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authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Marie-Laure
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mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D018920:Coculture Techniques; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D023281:Genomics; D006801:Humans; D054444:Immunoglobulin Light Chains, Surrogate / Q000235:genetics; D020128:Inhibitory Concentration 50; D053208:Kaplan-Meier Estimate; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D051757:PAX5 Transcription Factor / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D017384:Sequence Deletion; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D054444:Immunoglobulin Light Chains, Surrogate; D015514:Oncogene Proteins, Fusion; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; C578540:TCF3-HLF fusion protein, human; C515639:VPREB1 protein, human