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  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., 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.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-5FF1-B Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-5FF2-9
Genre: Journal Article

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© 2015 Macmillan Publishers Limited
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 Creators:
Fischer, U., Author
Forster, M., Author
Rinaldi, A., Author
Risch, T.1, Author
Sungalee, S., Author
Warnatz, H. J.1, Author              
Bornhauser, B., Author
Gombert, M., Author
Kratsch, C., Author
Stutz, A. M., Author
Sultan, M., Author
Tchinda, J., Author
Worth, C. L., Author
Amstislavskiy, V., Author
Badarinarayan, N., Author
Baruchel, A., Author
Bartram, T., Author
Basso, G., Author
Canpolat, C., Author
Cario, G., Author
Cave, H., AuthorDakaj, D., AuthorDelorenzi, M., AuthorDobay, M. P., AuthorEckert, C., AuthorEllinghaus, E., AuthorEugster, S., AuthorFrismantas, V., AuthorGinzel, S., AuthorHaas, O. A., AuthorHeidenreich, O., AuthorHemmrich-Stanisak, G., AuthorHezaveh, K., AuthorHoll, J. I., AuthorHornhardt, S., AuthorHusemann, P., AuthorKachroo, P., AuthorKratz, C. P., AuthorKronnie, G. T., AuthorMarovca, B., AuthorNiggli, F., AuthorMcHardy, A. C., AuthorMoorman, A. V., AuthorPanzer-Grumayer, R., AuthorPetersen, B. S., AuthorRaeder, B., AuthorRalser, M., AuthorRosenstiel, P., AuthorSchäfer, D., AuthorSchrappe, M., AuthorSchreiber, S., AuthorSchutte, M., AuthorStade, B., AuthorThiele, R., AuthorWeid, Nv, AuthorVora, A., AuthorZaliova, M., AuthorZhang, L., AuthorZichner, T., AuthorZimmermann, M., AuthorLehrach, H.2, Author              Borkhardt, A., AuthorBourquin, J. P., AuthorFranke, A., AuthorKorbel, J. O., AuthorStanulla, M., AuthorYaspo, M. L.1, Author               more..
Affiliations:
1Gene Regulation and Systems Biology of Cancer (Marie-Laure Yaspo), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2117287              
2Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433550              

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Free keywords: Animals Antineoplastic Agents/pharmacology/therapeutic use B-Cell-Specific Activator Protein/genetics Coculture Techniques Cohort Studies DNA Mutational Analysis Drug Resistance, Neoplasm Female Gene Expression Genetic Association Studies Genomics Humans Immunoglobulin Light Chains, Surrogate/genetics Inhibitory Concentration 50 Kaplan-Meier Estimate Male Mice, Inbred NOD Mice, SCID Mutation Oncogene Proteins, Fusion/*genetics/metabolism Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/*genetics/mortality Sequence Deletion Xenograft Model Antitumor Assays
 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.

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Language(s): eng - English
 Dates: 2015-07-272015-09
 Publication Status: Published in print
 Pages: 10
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1038/ng.3362
ISSN: 1546-1718 (Electronic)1061-4036 (Print)
 Degree: -

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Title: Nature Genetics
  Other : Nature Genet.
Source Genre: Journal
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Publ. Info: New York, NY : Nature America, Inc.
Pages: - Volume / Issue: 47 (9) Sequence Number: - Start / End Page: 1020 - 1029 Identifier: ISSN: 1061-4036
CoNE: https://pure.mpg.de/cone/journals/resource/954925598609