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.; Stütz, A.M.; Sultan, M.; Tchinda, J.; Worth, C.L.; Amstislavskiy, V.; Badarinarayan, N.; Baruchel, A.; Bartram, T.; Basso, G.; Canpolat, C.; Cario, G.; Cavé, 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.; Höll, J.I.; Hornhardt, S.; Husemann, P.; Kachroo, P.; Kratz, C.P.; Te Kronnie, G.; Marovca, B.; Niggli, F.; McHardy, A.C.; Moorman, A.V.; Panzer-Grümayer, R.; Petersen, B.S.; Raeder, B.; Ralser, M.; Rosenstiel, P.; Schäfer, D.; Schrappe, M.; Schreiber, S.; Schütte, M.; Stade, B.; Thiele, R.; von der Weid, N.; 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.

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

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Item Type:	Article
Title:	Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options
Creators:	Fischer, U., Forster, M., Rinaldi, A., Risch, T., Sungalee, S., Warnatz, H.J., Bornhauser, B., Gombert, M., Kratsch, C., Stütz, A.M., Sultan, M., Tchinda, J., Worth, C.L. ORCID: https://orcid.org/0000-0002-1796-9606, Amstislavskiy, V., Badarinarayan, N., Baruchel, A., Bartram, T., Basso, G., Canpolat, C., Cario, G., Cavé, 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., Höll, J.I., Hornhardt, S., Husemann, P., Kachroo, P., Kratz, C.P., Te Kronnie, G., Marovca, B., Niggli, F., McHardy, A.C., Moorman, A.V., Panzer-Grümayer, R., Petersen, B.S., Raeder, B., Ralser, M., Rosenstiel, P., Schäfer, D., Schrappe, M., Schreiber, S., Schütte, M., Stade, B., Thiele, R., von der Weid, N., Vora, A., Zaliova, M., Zhang, L., Zichner, T., Zimmermann, M., Lehrach, H., Borkhardt, A., Bourquin, J.P., Franke, A., Korbel, J.O., 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
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Volume:	47
Number:	9
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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