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Nature Research, Nature Genetics, 9(47), p. 1020-1029, 2015

DOI: 10.1038/ng.3362



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

Journal article published in 2015 by Nicolas von der Weid, Anna Rinaldi, Thomas Risch, Stéphanie Sungalee, Hans-Jörg Warnatz, Michael Gombert, Christina Kratsch, Adrian M. Stütz, Marc Sultan, Joelle Tchinda, Catherine L. Worth, Jessica I. Holl, Viktoras Frismantas, Sebastian Ginzel, Oskar A. Haas and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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 sensitiv