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Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options

U. Fischer, M. Forster, A. Rinaldi, T. Risch, S. Sungalee, HJ. Warnatz, B. Bornhauser, M. Gombert, C. Kratsch, AM. Stütz, M. Sultan, J. Tchinda, CL. Worth, V. Amstislavskiy, N. Badarinarayan, A. Baruchel, T. Bartram, G. Basso, C. Canpolat, G....

. 2015 ; 47 (9) : 1020-9. [pub] 20150727

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc16010028
E-zdroje Online Plný text

NLK ProQuest Central od 2000-01-01 do Před 1 rokem
Medline Complete (EBSCOhost) od 1998-06-01 do 2015-11-30
Health & Medicine (ProQuest) od 2000-01-01 do Před 1 rokem
Public Health Database (ProQuest) od 2000-01-01 do Před 1 rokem

Odkazy

PubMed 26214592
DOI 10.1038/ng.3362
Knihovny.cz E-zdroje

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.

Alacris Theranostics GmbH Berlin Germany

Children's Cancer Research Institute Vienna Austria

Clinic for Pediatric Oncology Hematology and Clinical Immunology Medical Faculty Heinrich Heine University Düsseldorf Germany

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

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

Department of Algorithmic Bioinformatics Heinrich Heine University Düsseldorf Germany

Department of Computer Science Bonn Rhine Sieg University of Applied Sciences Sankt Augustin Germany

Department of Genetics Hôpital Robert Debré and Paris Diderot University Paris France

Department of Pediatric Hemato Immunology Hôpital Robert Debré and Paris Diderot University Paris France

Department of Pediatrics Acy`badem University Medical School Atas¸ehir Istanbul Turkey

Department of Pediatrics Christian Albrechts University of Kiel and University Medical Center Schleswig Holstein Kiel Germany

Department of Pediatrics Laboratory of Pediatric Hematology Oncology University of Padova Padova Italy

Department of Vertebrate Genomics Max Planck Institute for Molecular Genetics Berlin Germany

Department of Vertebrate Genomics Max Planck Institute for Molecular Genetics Berlin Germany Alacris Theranostics GmbH Berlin Germany Dahlem Centre for Genome Research and Medical Systems Biology Berlin Germany

European Molecular Biology Laboratory Genome Biology Unit Heidelberg Germany

Federal Office for Radiation Protection Oberschleissheim Germany

Institute of Clinical Molecular Biology Christian Albrechts University of Kiel Kiel Germany

Ludwig Center for Cancer Research University of Lausanne Lausanne Switzerland Swiss Institute for Bioinformatics Lausanne Switzerland

Northern Institute of Cancer Research Newcastle University Newcastle upon Tyne United Kingdom

Pediatric Hematology and Oncology Charité University Hospital Berlin Germany

Pediatric Hematology and Oncology Hannover Medical School Hannover Germany

Pediatric Hematology and Oncology Hannover Medical School Hannover Germany Childhood Leukaemia Investigation Prague Department of Pediatric Hematology Oncology 2nd Faculty of Medicine Charles University Prague Prague Czech Republic

Pediatric Oncology Children's Research Centre University Children's Hospital Zurich Zurich Switzerland

Sheffield Children's Hospital Sheffield United Kingdom

Swiss Institute for Bioinformatics Lausanne Switzerland

Universitäts Kinderspital beider Basel Basel Switzerland

Citace poskytuje Crossref.org

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