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

U. Fischer; M. Forster; A. Rinaldi; T. Risch; S. Sungalee; H.J. Warnatz; B. Bornhauser; M. Gombert; C. Kratsch; A.M. Stütz; M. Sultan; J. Tchinda; C.L. Worth; V. Amstislavskiy; N. Badarinarayan; A. Baruchel; T. Bartram; G. Basso; C. Canpolat; G. Cario; H. Cavé; D. Dakaj; M. Delorenzi; M.P. Dobay; C. Eckert; E. Ellinghaus; S. Eugster; V. Frismantas; S. Ginzel; O.A. Haas; O. Heidenreich; G. Hemmrich-Stanisak; K. Hezaveh; J.I. Höll; S. Hornhardt; P. Husemann; P. Kachroo; C.P. Kratz; G.T. Kronnie; B. Marovca; F. Niggli; A.C. McHardy; A.V. Moorman; R. Panzer-Grümayer; B.S. Petersen; B. Raeder; M. Ralser; P. Rosenstiel; D. Schäfer; M. Schrappe; S. Schreiber; M. Schütte; B. Stade; R. Thiele; N.v. Weid; A. Vora; M. Zaliova; L. Zhang; T. Zichner; M. Zimmermann; H. Lehrach; A. Borkhardt; J.P. Bourquin; A. Franke; J.O. Korbel; M. Stanulla; M.L. Yaspo

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

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Date

2015

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Articles

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Langue

Anglais

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doi: 10.1038/ng.3362
issn: 1061-4036

Source

Serveur académique Lausannois

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Ce document est lié à :
info:eu-repo/semantics/altIdentifier/doi/10.1038/ng.3362

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info:eu-repo/semantics/altIdentifier/pmid/26214592

Ce document est lié à :
info:eu-repo/semantics/altIdentifier/eissn/1546-1718

Ce document est lié à :
info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_32F6C5ED54867

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Serveur Académique Lausannois

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Université de Lausanne et CHUV

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info:eu-repo/semantics/openAccess , Copying allowed only for non-profit organizations , https://serval.unil.ch/disclaimer

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Leukemia, Lymphoblastic Acute lymphocytic leukemia

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U. Fischer et al., « Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options. », Serveur académique Lausannois, ID : 10.1038/ng.3362

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

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