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

Nature genetics ·Vol. 47 ·No. 9 ·2016-01-13

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

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.

Article Info

Journal

Nature genetics

Abbr.

Nat Genet

ISSN

1061-4036

Published

2016-01-13

Indexed

2015-08-28

Updated

2016-11-25

Language

English

Country/Region

United States

NLM ID

9216904

External Links

PubMed source View journal details

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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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