Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options
dc.contributor.author | Fischer, Ute | |
dc.contributor.author | Forster, Michael | |
dc.contributor.author | Rinaldi, Anna | |
dc.contributor.author | Risch, Thomas | |
dc.contributor.author | Sungalee, Stephanie | |
dc.contributor.author | Warnatz, Hans-Joerg | |
dc.contributor.author | Bornhauser, Beat | |
dc.contributor.author | Gombert, Michael | |
dc.contributor.author | Kratsch, Christina | |
dc.contributor.author | Stuetz, Adrian M. | |
dc.contributor.author | Sultan, Marc | |
dc.contributor.author | Tchinda, Joelle | |
dc.contributor.author | Worth, Catherine L. | |
dc.contributor.author | Amstislavskiy, Vyacheslav | |
dc.contributor.author | Badarinarayan, Nandini | |
dc.contributor.author | Baruchel, Andre | |
dc.contributor.author | Bartram, Thies | |
dc.contributor.author | Basso, Giuseppe | |
dc.contributor.author | Canpolat, Cengiz | |
dc.contributor.author | Cario, Gunnar | |
dc.contributor.author | Cave, Helene | |
dc.contributor.author | Dakaj, Dardane | |
dc.contributor.author | Delorenzi, Mauro | |
dc.contributor.author | Dobay, Maria Pamela | |
dc.contributor.author | Eckert, Cornelia | |
dc.contributor.author | Ellinghaus, Eva | |
dc.contributor.author | Eugster, Sabrina | |
dc.contributor.author | Frismantas, Viktoras | |
dc.contributor.author | Ginzel, Sebastian | |
dc.contributor.author | Haas, Oskar A. | |
dc.contributor.author | Heidenreich, Olaf | |
dc.contributor.author | Hemmrich-Stanisak, Georg | |
dc.contributor.author | Hezaveh, Kebria | |
dc.contributor.author | Hoell, Jessica I. | |
dc.contributor.author | Hornhardt, Sabine | |
dc.contributor.author | Husemann, Peter | |
dc.contributor.author | Kachroo, Priyadarshini | |
dc.contributor.author | Kratz, Christian P. | |
dc.contributor.author | te Kronnie, Geertruy | |
dc.contributor.author | Marovca, Blerim | |
dc.contributor.author | Niggli, Felix | |
dc.contributor.author | McHardy, Alice C. | |
dc.contributor.author | Moorman, Anthony V. | |
dc.contributor.author | Panzer-Gruemayer, Renate | |
dc.contributor.author | Petersen, Britt S. | |
dc.contributor.author | Raeder, Benjamin | |
dc.contributor.author | Ralser, Meryem | |
dc.contributor.author | Rosenstiel, Philip | |
dc.contributor.author | Schaefer, Daniel | |
dc.contributor.author | Schrappe, Martin | |
dc.contributor.author | Schreiber, Stefan | |
dc.contributor.author | Schuette, Moritz | |
dc.contributor.author | Stade, Bjoern | |
dc.contributor.author | Thiele, Ralf | |
dc.contributor.author | von der Weid, Nicolas | |
dc.contributor.author | Vora, Ajay | |
dc.contributor.author | Zaliova, Marketa | |
dc.contributor.author | Zhang, Langhui | |
dc.contributor.author | Zichner, Thomas | |
dc.contributor.author | Zimmermann, Martin | |
dc.contributor.author | Lehrach, Hans | |
dc.contributor.author | Borkhardt, Arndt | |
dc.contributor.author | Bourquin, Jean-Pierre | |
dc.contributor.author | Franke, Andre | |
dc.contributor.author | Korbel, Jan O. | |
dc.contributor.author | Stanulla, Martin | |
dc.contributor.author | Yaspo, Marie-Laure | |
dc.date.accessioned | 2023-02-21T12:42:22Z | |
dc.date.available | 2023-02-21T12:42:22Z | |
dc.date.issued | 2015-01-01 | |
dc.description.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. | |
dc.description.issue | 9 | |
dc.description.issue | SEP | |
dc.description.pages | 1020+ | |
dc.description.volume | 47 | |
dc.identifier.doi | 10.1038/ng.3362 | |
dc.identifier.uri | https://hdl.handle.net/11443/2808 | |
dc.identifier.uri | http://dx.doi.org/10.1038/ng.3362 | |
dc.identifier.wos | WOS:000360394100012 | |
dc.publisher | NATURE PUBLISHING GROUP | |
dc.relation.ispartof | NATURE GENETICS | |
dc.title | Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options | |
dc.type | Article |
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