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Nat Genet. 2015 Sep;47(9):1020-1029. doi: 10.1038/ng.3362. Epub 2015 Jul 27.

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

Author information

1
Clinic for Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
2
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
3
Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
4
Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
5
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
6
Department of Algorithmic Bioinformatics, Heinrich-Heine-University, Düsseldorf, Germany.
7
Department of Pediatric Hemato-Immunology, Hôpital Robert Debré and Paris Diderot University, Paris, France.
8
Department of Pediatrics, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
9
Department of Pediatrics, Laboratory of Pediatric Hematology/Oncology, University of Padova, Padova, Italy.
10
Department of Pediatrics, Acıbadem University Medical School, Ataşehir, Istanbul, Turkey.
11
Department of Genetics, Hôpital Robert Debré and Paris Diderot University, Paris, France.
12
Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland.
13
Swiss Institute for Bioinformatics (SIB), Lausanne, Switzerland.
14
Pediatric Hematology and Oncology, Charité University Hospital, Berlin, Germany.
15
Department of Computer Science, Bonn-Rhine-Sieg University of Applied Sciences, Sankt Augustin, Germany.
16
Children's Cancer Research Institute, Vienna, Austria.
17
Northern Institute of Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
18
Federal Office for Radiation Protection, Oberschleissheim, Germany.
19
Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
20
Alacris Theranostics GmbH, Berlin, Germany.
21
Universitäts-Kinderspital beider Basel (UKBB), Basel, Switzerland.
22
Sheffield Children's Hospital, Sheffield, United Kingdom.
23
Childhood Leukaemia Investigation Prague (CLIP), Department of Pediatric Hematology/Oncology, Second Faculty of Medicine, Charles University Prague, Prague, Czech Republic.
24
Department of Hematology, Union Hospital, Fujian Medical University, Fuzhou, China.
25
Dahlem Centre for Genome Reseach and Medical Systems Biology, Berlin, Germany.
#
Contributed equally

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.

PMID:
26214592
PMCID:
PMC4603357
DOI:
10.1038/ng.3362
[Indexed for MEDLINE]
Free PMC Article

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