GENOMIC AND DRUG RESPONSE PROFILING OF FATAL TCF3-HLF-POSITIVE PEDIATRIC ACUTE LYMPHOBLASTICLEUKEMIA IDENTIFIES RECURRENT MUTATION PATTERNS AND NOVEL THERAPEUTIC OPTIONS
Author(s): ,
Jean-Pierre Bourquin
Affiliations:
Pediatric Oncology,University Children's Hospital,Zurich,Switzerland
,
Ute Fischer
Affiliations:
Clinic for Pediatric Oncology, Hematology, and Clinical Immunology,Heinrich-Heine-University,Düsseldorf,Germany
,
Michael Forster
Affiliations:
Institute of Clinical Molecular Biology,Christian-Albrechts-University,Kiel,Germany
,
Anna Rinaldi
Affiliations:
Pediatric Oncology,University Children's Hospital,Zurich,Switzerland
,
Thomas Risch
Affiliations:
Department of Vertebrate Genomics,Max Planck Institute for Molecular Genetics,Berlin,Germany
,
Stephanie Sungalee
Affiliations:
Genome Biology Unit,European Molecular Biology Laboratory,Heidelberg,Germany
,
Warnatz Hans-Jörg
Affiliations:
Department of Vertebrate Genomics,Max Planck Institute for Molecular Genetics,Berlin,Germany
,
Beat Bornhauser
Affiliations:
Pediatric Oncology,University Children's Hospital,Zurich,Switzerland
,
Gombert Michael
Affiliations:
Clinic for Pediatric Oncology, Hematology, and Clinical Immunology,Heinrich-Heine-University,Düsseldorf,Germany
,
Kratsch Christina
Affiliations:
Clinic for Pediatric Oncology, Hematology, and Clinical Immunology,Heinrich-Heine-University,Düsseldorf,Germany
,
Stütz Adrian
Affiliations:
Genome Biology Unit,European Molecular Biology Laboratory,Heidelberg,Germany
,
Sultan Marc
Affiliations:
Department of Vertebrate Genomics,Max Planck Institute for Molecular Genetics,Berlin,Germany
,
Worth Catherine
Affiliations:
Department of Vertebrate Genomics,Max Planck Institute for Molecular Genetics,Berlin,Germany
,
Vyacheslav Amstislavskiy
Affiliations:
Department of Vertebrate Genomics,Max Planck Institute for Molecular Genetics,Berlin,Germany
,
André Baruchel
Affiliations:
Department of Pediatric Hemato-Immunology,Hôpital Robert Debré and Paris Diderot University,Paris,France
,
Bartram Thies
Affiliations:
Department of Pediatrics,University Hospital Schleswig-Holstein,Kiel,Germany
,
Basso giuseppe
Affiliations:
Department of Pediatrics,University of Padova,Padova,Italy
,
Cario Gunnar
Affiliations:
Department of Pediatrics,University Hospital Schleswig-Holstein,Kiel,Germany
,
Cavé Hélène
Affiliations:
Department of Genetics,Hôpital Robert Debré and Paris Diderot University,Paris,France
,
Dakaj Dardane
Affiliations:
Pediatric Oncology,University Children's Hospital,Zurich,Switzerland
,
Delorenzi Mauro
Affiliations:
SIB Swiss Institute for Bioinformatics,Ludwig Center for Cancer Research, University of Lausanne,Lausanne,Switzerland
,
Maria Pamela Dobay
Affiliations:
SIB Swiss Institute for Bioinformatics,Ludwig Center for Cancer Research, University of Lausanne,Lausanne,Switzerland
,
Cornelia Eckert
Affiliations:
Pediatric Hematology and Oncology,Charité University Hospital,Berlin,Germany
,
Eva Ellinghaus
Affiliations:
Institute of Clinical Molecular Biology,Christian-Albrechts-University,Kiel,Germany
,
Sabrina Eugster
Affiliations:
pediatric Oncology,University Children's Hospital,Zurich,Switzerland
,
Viktoras Frismantas
Affiliations:
Pediatric Oncology,University Children's Hospital,Zurich,Switzerland
,
Sebastian Ginzel
Affiliations:
Clinic for Pediatric Oncology, Hematology, and Clinical Immunology,Heinrich-Heine-University,Düsseldorf,Germany
,
Oskar Haas
Affiliations:
St. Anna Children’s Hospital and Children’s Cancer Research Institute,Vienna,Austria
,
Olaf Heidenreich
Affiliations:
Department of Molecular Haematology,Northern Institute for Cancer Research,Newcastle,United Kingdom
,
Georg Hemmrich-Stanisak
Affiliations:
Institute of Clinical Molecular Biology,Christian-Albrechts-University,Kiel,Germany
,
Kebriah Hezaveh
Affiliations:
Clinic for Pediatric Oncology, Hematology, and Clinical Immunology,Medical Faculty, Heinrich-Heine-University,Düsseldorf,Germany
,
Jessica Höll
Affiliations:
Clinic for Pediatric Oncology, Hematology, and Clinical Immunology,Heinrich-Heine-University,Düsseldorf,Germany
,
Sabine Hornhardt
Affiliations:
Federal Office for Radiation Protection,Oberschleissheim,Germany
,
Peter Husemann
Affiliations:
Clinic for Pediatric Oncology, Hematology, and Clinical Immunology,Heinrich-Heine-University,Düsseldorf,Germany
,
Geertruy te Kronnie
Affiliations:
Department of Pediatrics,University of Padova,Padova,Italy
,
Hans Lehrach
Affiliations:
Department of Vertebrate Genomics,Max Planck Institute for Molecular Genetics,Berlin,Germany
,
Blerim Marovca
Affiliations:
Pediatric Oncology,University Children's Hospital,Zurich,Switzerland
,
Felix Niggli
Affiliations:
pediatric Oncology,University Children's Hospital,Zurich,Switzerland
,
Alice McHardy
Affiliations:
Department of Algorithmic Bioinformatics,Heinrich-Heine-University,Düsseldorf,Germany
,
Anthony Moorman
Affiliations:
Northern Institute of Cancer Research,Newcastle University,Newcastle,United Kingdom
,
Renate Panzer-Grümayer
Affiliations:
St. Anna Children’s Hospital and Children’s Cancer Research Institute,Vienna,Austria
,
Britt S. Petersen
Affiliations:
Institute of Clinical Molecular Biology,Christian-Albrechts-University,Kiel,Germany
,
Benjamin Raeder
Affiliations:
Genome Biology Unit,European Molecular Biology Laboratory,Heidelberg,Germany
,
Meryem Ralser
Affiliations:
Department of Vertebrate Genomics,Max Planck Institute for Molecular Genetics,Berlin,Germany
,
Philip Rosenstiel
Affiliations:
Institute of Clinical Molecular Biology,Christian-Albrechts-University,Kiel,Germany
,
Daniel Schäfer
Affiliations:
Clinic for Pediatric Oncology, Hematology, and Clinical Immunology,Heinrich-Heine-University,Düsseldorf,Germany
,
Martin Schrappe
Affiliations:
Department of Pediatrics,University Hospital Schleswig-Holstein,Kiel,Germany
,
Stefan Schreiber
Affiliations:
Institute of Clinical Molecular Biology,Christian-Albrechts-University,Kiel,Germany
,
Moritz Schütte
Affiliations:
Alacris Theranostics GmbH,Berlin,Germany
,
Björn Stade
Affiliations:
Institute of Clinical Molecular Biology,Christian-Albrechts-University,Kiel,Germany
,
Joelle Tchinda
Affiliations:
Pediatric Oncology,University Children's Hospital,Zurich,Switzerland
,
Ralf Thiele
Affiliations:
Department of Computer Science,Bonn-Rhine-Sieg University of Applied Sciences,Sankt Augustin,Germany
,
Ajay Vora
Affiliations:
Sheffield Children's Hospital,Sheffield,United Kingdom
,
Marketa Zaliova
Affiliations:
Department of Pediatric Hematology/Oncology,Charles University Prague,Prague,Czech Republic
,
Thomas Zichner
Affiliations:
Genome Biology Unit,European Molecular Biology Laboratory,Heidelberg,Germany
,
Martin Zimmermann
Affiliations:
Pediatric Hematology and Oncology,Hannover Medical School,Hannover,Germany
,
Arndt Borkhardt
Affiliations:
Clinic for Pediatric Oncology, Hematology, and Clinical Immunology,Heinrich-Heine-University,Düsseldorf,Germany
,
Andre Franke
Affiliations:
Institute of Clinical Molecular Biology ,Christian-Albrechts-University,Kiel,Germany
,
Jan O. Korbel
Affiliations:
Genome Biology Unit,European Molecular Biology Laboratory,Heidelberg,Germany
,
Martin Stanulla
Affiliations:
Pediatric Hematology and Oncology,Hannover Medical School,Hannover,Germany
Marie-Laure Yaspo
Affiliations:
Department of Vertebrate Genomics,Max Planck Institute for Molecular Genetics,Berlin,Germany
EHA Library. Bourquin J. Jun 13, 2015; 103182; S520 Disclosure(s): KINDERSPITAL ZÜRICH
Jean-Pierre Bourquin
Jean-Pierre Bourquin
Contributions
×
Abstract
Abstract: S520

Type: Oral Presentation

Presentation during EHA20: From 13.06.2015 16:45 to 13.06.2015 17:00

Location: Room Lehar 1 + 2

Background
The translocation t(17;19)(q22;p13) results in the fusion of the transactivating domain of the B cell transcription factor TCF3 and the DNA binding domain of the hepatic leukemia factor HLF. TCF3-HLF defines a rare subtype of ALL that is currently incurable. In contrast, the fusion of the same portion of TCF3 to the PBX1 gene (t(1;19)) results in a leukemia subtype with a favorable prognosis. TCF3-HLF ALL constitutes a paradigm of treatment refractory leukemia in which the oncogenic fusion protein drives programs that are fundamental for the malignant process. However genetic engineering experiments in mice did not recapitulate disease, suggesting that the cellular context in which the translocation occurs is critical for transformation. 

Aims
We explored the genetic landscape of ten TCF3-HLF positive ALL cases in comparison to TCF3-PBX1 positive ALL using primary diagnostic samples and corresponding patient derived leukemia xenografts in order to analyze whether TCF3-HLF is associated with characteristic patterns of genomic lesions and to establish a well characterized humanized mouse model for functional investigations.

Methods
We used an integrated multi-OMICs approach to identify mutation and gene expression patterns in TCF3-HLF- and TCF3-PBX1-positiveALL. To compare drug response profiles of treatment resistant TCF3-HLF-positive and responsive TCF3-PBX1-positive ALL we established a xenograft model of patient derived leukemia. At least two biological replicates per case were xenografted in NOD/SCID/IL2rγnull (NSG) mice. Drug response profiles to a customized library of >100 therapeutic compounds were obtained and in vivo validation studies were performed using this model.

Results
In TCF3-HLF-positive ALL, intragenic deletions in the lymphoid transcription factor PAX5 or somatic mutations in the non-translocated allele of TCF3 (acting upstream of PAX5), but not in any of the IFKZ family members, were recurrent and frequently observed in conjunction with RAS pathway aberrations. The pattern of co-occurring mutations was not overlapping in TCF3-PBX1 ALL, supporting the notion that completely different genetic interactions may be required for disease pathogenesis. The profile of mutations was maintained in the corresponding xenografts. Sequence features at the translocation breakpoints suggested RAG mediated recombination and an already lymphoid-committed cell of origin, but the TCF3-HLF-positive ALL transcriptome was enriched for stem cell and myeloid features, consistent with reprogramming towards a hybrid, more drug-resistant hematopoietic state. This gene expression signature was maintained in matched patient-derived xenografts. TCF3-HLF-positive ALL revealed a distinct drug-response profile with resistance to some agents commonly used in ALL therapy, but sensitivity towards glucocorticoids and some therapeutic agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor ABT-199 indicating BCL2-dependency of TCF3-HLF-positive ALL. Our results show, that ABT-199 acts synergistically with conventional chemotherapeutic agents, including dexamethasone and vincristine, providing a rationale for experimental therapy.

Summary
The molecular portrait of TCF3-HLF-positive ALL indicates that the initiating event occurs in cells committed to the lymphoid lineage and that leukemogenesis requires a restricted pattern of additional genetic lesions. Maintenance of dominant genomic and transcriptomic patterns of both TCF3-translocated subtypes in the corresponding xenografts provides the basis for systematic functional investigations. Integration of drug response profiling revealed recurrent patterns of resistance and new options for the treatment of this deadly disease.

Keyword(s): Acute lymphoblastic leukemia, Drug resistance, Drug sensitivity, Xenotransplantation

Session topic: Biological pathway deregulation in B Cell Precursor ALL

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