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


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.

SUBMITTER: Fischer U 

PROVIDER: S-EPMC4603357 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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

Fischer Ute U   Forster Michael M   Rinaldi Anna A   Risch Thomas T   Sungalee Stéphanie S   Warnatz Hans-Jörg HJ   Bornhauser Beat B   Gombert Michael M   Kratsch Christina C   Stütz Adrian M AM   Sultan Marc M   Tchinda Joelle J   Worth Catherine L CL   Amstislavskiy Vyacheslav V   Badarinarayan Nandini N   Baruchel André A   Bartram Thies T   Basso Giuseppe G   Canpolat Cengiz C   Cario Gunnar G   Cavé Hélène H   Dakaj Dardane D   Delorenzi Mauro M   Dobay Maria Pamela MP   Eckert Cornelia C   Ellinghaus Eva E   Eugster Sabrina S   Frismantas Viktoras V   Ginzel Sebastian S   Haas Oskar A OA   Heidenreich Olaf O   Hemmrich-Stanisak Georg G   Hezaveh Kebria K   Höll Jessica I JI   Hornhardt Sabine S   Husemann Peter P   Kachroo Priyadarshini P   Kratz Christian P CP   Te Kronnie Geertruy G   Te Kronnie Geertruy G   Marovca Blerim B   Niggli Felix F   McHardy Alice C AC   Moorman Anthony V AV   Panzer-Grümayer Renate R   Petersen Britt S BS   Raeder Benjamin B   Ralser Meryem M   Rosenstiel Philip P   Schäfer Daniel D   Schrappe Martin M   Schreiber Stefan S   Schütte Moritz M   Stade Björn B   Thiele Ralf R   von der Weid Nicolas N   Vora Ajay A   Zaliova Marketa M   Zhang Langhui L   Zichner Thomas T   Zimmermann Martin M   Lehrach Hans H   Borkhardt Arndt A   Bourquin Jean-Pierre JP   Franke Andre A   Korbel Jan O JO   Stanulla Martin M   Yaspo Marie-Laure ML  

Nature genetics 20150727 9


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 cooperati  ...[more]

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