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

  • 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.

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Metadaten
Document Type:Article
Language:English
Author:Ute Fischer, Michael Forster, Anna Rinaldi, Thomas Risch, Stéphanie Sungalee, Hans-Jörg Warnatz, Beat Bornhauser, Michael Gombert, Christina Kratsch, Adrian M. Stütz, Marc Sultan, Joelle Tchinda, Catherine L. Worth, Vyacheslav Amstislavskiy, Nandini Badarinarayan, André Baruchel, Thies Bartram, Giuseppe Basso, Cengiz Canpolat, Gunnar Cario, Hélène Cavé, Dardane Dakaj, Mauro Delorenzi, Maria Pamela Dobay, Cornelia Eckert, Eva Ellinghaus, Sabrina Eugster, Viktoras Frismantas, Sebastian Ginzel, Oskar A. Haas, Olaf Heidenreich, Georg Hemmrich-Stanisak, Kebria Hezaveh, Jessica I. Höll, Sabine Hornhardt, Peter Husemann, Priyadarshini Kachroo, Christian P. Kratz, Geertruy Te Kronnie, Blerim Marovca, Felix Niggli, Alice C. McHardy, Anthony V. Moorman, Renate Panzer-Grümayer, Britt S. Petersen, Benjamin Raeder, Meryem Ralser, Philip Rosenstiel, Daniel Schäfer, Martin Schrappe, Stefan Schreiber, Moritz Schütte, Björn Stade, Ralf Thiele, Nicolas von der Weid, Ajay Vora, Marketa Zaliova, Langhui Zhang, Thomas Zichner, Martin Zimmermann, Hans Lehrach, Arndt Borkhardt, Jean-Pierre Bourquin, Andre Franke, Jan O. Korbel, Martin Stanulla, Marie-Laure Yaspo
Parent Title (English):Nat Genet. (Nature Genetics)
Volume:47
Issue:9
First Page:1020
Last Page:1029
ISSN:1061-4036
DOI:https://doi.org/10.1038/ng.3362
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=26214592
Publisher:Nature Publishing Group
Date of first publication:2015/07/27
Departments, institutes and facilities:Fachbereich Informatik
Institut für funktionale Gen-Analytik (IFGA)
Dewey Decimal Classification (DDC):5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 576 Genetik und Evolution
Entry in this database:2015/08/21