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

Lookup NU author(s): Professor Olaf Heidenreich, Professor Anthony MoormanORCiD

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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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Author(s): Fischer U, Forster M, Rinaldi A, Risch T, Sungalee S, Warnatz HJ, Bornhauser B, Gombert M, Kratsch C, Stutz AM, Sultan M, Tchinda J, Worth CL, Amstislavskiy V, Badarinarayan N, Baruchel A, Bartram T, Basso G, Canpolat C, Cario G, Cave H, Dakaj D, Delorenzi M, Dobay MP, Eckert C, Ellinghaus E, Eugster S, Frismantas V, Ginzel S, Haas OA, Heidenreich O, Hemmrich-Stanisak G, Hezaveh K, Holl JI, Hornhardt S, Husemann P, Kachroo P, Kratz CP, te Kronnie G, Marovca B, Niggli F, McHardy AC, Moorman AV, Panzer-Grumayer R, Petersen BS, Raeder B, Ralser M, Rosenstiel P, Schafer D, Schrappe M, Schreiber S, Schutte M, Stade B, Thiele R, von der Weid N, Vora A, Zaliova M, Zhang LH, Zichner T, Zimmermann M, Lehrach H, Borkhardt A, Bourquin JP, Franke A, Korbel JO, Stanulla M, Yaspo ML

Publication type: Article

Publication status: Published

Journal: Nature Genetics

Year: 2015

Volume: 47

Issue: 9

Pages: 1020-1029

Print publication date: 01/09/2015

Online publication date: 27/07/2015

Acceptance date: 29/06/2015

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/ng.3362

DOI: 10.1038/ng.3362

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