GENOMIC AND DRUG RESPONSE PROFILING OF FATAL TCF3-HLF-POSITIVE PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA IDENTIFIES RECURRENT MUTATION PATTERNS AND NOVEL THERAPEUTIC OPTIONS.

Bourquin, J. P., Fischer, U., Forster, M., Rinaldil, A., Risch, T., Sungalee, S., Hans-Joerg, W., Bornhauser, B., Michael, G., Christina, K., Adrian, S., Marc, S., Catherine, W., Amstislavskiy, V., Baruchel, A., Thies, B., Giuseppe, B., Gunnar, C., Helene, C., Dardanel, D., Mauro, D., Dobay, M. P., Eckert, C., Ellinghaus, E., Eugster, S., Frismantas, V., Ginzel, S., Haas, O., Heidenreich, O., Hemmrich-Stanisak, G., Hezaveh, K., Hoell, J., Homhardt, S., Husemann, P., te Kronnie, G., Lehrach, H., Marovca, B., Niggli, F., McHardy, A., Moorman, A., Panzer-Gruemayer, R., Petersen, B. S., Raeder, B., Ralser, M., Rosenstiel, Philip, Schaefer, D., Schrappe, M., Schreiber, Stefan, Schuette, M., Stade, B., Tchindal, J., Thiele, R., Vora, A., Zaliova, M., Zichner, T., Zimmermann, M., Borkhardt, A., Franke, Andre, Korbel, J. O., Stanulla, M. and Yaspo, M. L. (2015) GENOMIC AND DRUG RESPONSE PROFILING OF FATAL TCF3-HLF-POSITIVE PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA IDENTIFIES RECURRENT MUTATION PATTERNS AND NOVEL THERAPEUTIC OPTIONS. Haematologica, 100 . p. 197. DOI 10.1038/ng.3362.

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Supplementary data:

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.

Document Type: Article
Additional Information: Times Cited: 0 1 20th Congress of European-Hematology-Association Jun 11-14, 2015 Vienna, AUSTRIA
Keywords: Acute lymphocytic leukaemia, Personalized medicine
Research affiliation: Kiel University > Kiel Marine Science
OceanRep > The Future Ocean - Cluster of Excellence
Kiel University
Refereed: Yes
Open Access Journal?: No
DOI etc.: 10.1038/ng.3362
ISSN: 0390-6078
Projects: Future Ocean
Date Deposited: 20 Oct 2016 10:59
Last Modified: 29 Aug 2019 10:32
URI: http://oceanrep.geomar.de/id/eprint/32423

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