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

Fischer, U.; Forster, M.; Rinaldi, A.; Risch, T.; Sungalee, S.; Warnatz, H. J.; Bornhauser, B.; Gombert, M.; Kratsch, C.; Stutz, A. M.; Sultan, M.; Tchinda, J.; Worth, C. L.; Amstislavskiy, V.; Badarinarayan, N.; Baruchel, A.; Bartram, T.; Basso, G.; Canpolat, C.; Cario, G.; Cave, H.; Dakaj, D.; Delorenzi, M.; Dobay, M. P.; Eckert, C.; Ellinghaus, E.; Eugster, S.; Frismantas, V.; Ginzel, S.; Haas, O. A.; Heidenreich, O.; Hemmrich-Stanisak, G.; Hezaveh, K.; Holl, J. I.; Hornhardt, S.; Husemann, P.; Kachroo, P.; Kratz, C. P.; Kronnie, G. T.; Marovca, B.; Niggli, F.; McHardy, A. C.; Moorman, A. V.; Panzer-Grumayer, R.; Petersen, B. S.; Raeder, B.; Ralser, M.; Rosenstiel, P.; Schäfer, D.; Schrappe, M.; Schreiber, S.; Schutte, M.; Stade, B.; Thiele, R.; Weid, Nv; Vora, A.; Zaliova, M.; Zhang, L.; Zichner, T.; Zimmermann, M.; Lehrach, H.; Borkhardt, A.; Bourquin, J. P.; Franke, A.; Korbel, J. O.; Stanulla, M.; Yaspo, M. L.

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

MPS-Authors

Risch, T.
Gene Regulation and Systems Biology of Cancer (Marie-Laure Yaspo), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Warnatz, H. J.
Gene Regulation and Systems Biology of Cancer (Marie-Laure Yaspo), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Lehrach, H.
Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Yaspo, M. L.
Gene Regulation and Systems Biology of Cancer (Marie-Laure Yaspo), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Fischer, U., Forster, M., Rinaldi, A., Risch, T., Sungalee, S., Warnatz, H. J., et al. (2015). Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options. Nature Genetics, 47(9), 1020-1029. doi:10.1038/ng.3362.

Cite as: https://hdl.handle.net/11858/00-001M-0000-002A-5FF1-B

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.