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 Name:	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. 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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