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

Item Type:Article
Title:Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options
Creators Name:Fischer, U. and Forster, M. and Rinaldi, A. and Risch, T. and Sungalee, S. and Warnatz, H.J. and Bornhauser, B. and Gombert, M. and Kratsch, C. and Stütz, A.M. and Sultan, M. and Tchinda, J. and Worth, C.L. and Amstislavskiy, V. and Badarinarayan, N. and Baruchel, A. and Bartram, T. and Basso, G. and Canpolat, C. and Cario, G. and Cavé, H. and Dakaj, D. and Delorenzi, M. and Dobay, M.P. and Eckert, C. and Ellinghaus, E. and Eugster, S. and Frismantas, V. and Ginzel, S. and Haas, O.A. and Heidenreich, O. and Hemmrich-Stanisak, G. and Hezaveh, K. and Höll, J.I. and Hornhardt, S. and Husemann, P. and Kachroo, P. and Kratz, C.P. and Te Kronnie, G. and Marovca, B. and Niggli, F. and McHardy, A.C. and Moorman, A.V. and Panzer-Grümayer, R. and Petersen, B.S. and Raeder, B. and Ralser, M. and Rosenstiel, P. and Schäfer, D. and Schrappe, M. and Schreiber, S. and Schütte, M. and Stade, B. and Thiele, R. and von der Weid, N. and Vora, A. and Zaliova, M. and Zhang, L. and Zichner, T. and Zimmermann, M. and Lehrach, H. and Borkhardt, A. and Bourquin, J.P. and Franke, A. and Korbel, J.O. and Stanulla, M. and Yaspo, M.L.
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.
Keywords:Acute Lymphocytic Leukaemia, Personalized Medicine, Animals, Mice
Source:Nature Genetics
Publisher:Nature Publishing Group
Page Range:1020-1029
Date:September 2015
Official Publication:https://doi.org/10.1038/ng.3362
PubMed:View item in PubMed

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