Item Type: | Article |
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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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