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

Nature Genetics volume 47, pages 10201029 (2015) | Download Citation

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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Acknowledgements

We thank all participants and personnel involved in the clinical trials in Austria, France, Germany, United Kingdom and Switzerland. We thank T. Radimerski and Novartis for providing essential compounds. We thank the Leukaemia & Lymphoma Research (LLR) Childhood Leukaemia Cell Bank in the UK for providing primary patient samples. This work was supported by the German Federal Office for Radiation Protection (grant St.Sch. 3611S70014), by the Swiss National Research Foundation SNF 310030-133108, the foundation 'Kinderkrebsforschung Schweiz', the 'Krebsliga Zurich', the Sassella Foundation, the Fondation Panacée, the clinical research focus program 'Human Hemato-Lymphatic Diseases' of the University of Zurich, the Deutsche Forschungsgemeinschaft (DFG), Clusters of Excellence 'Inflammation at Interfaces', the EU Seventh Framework Program (FP7/2007-2013, grant 262055, ESGI; FP7-HEALTH-F2-2011 grant 261474, ENCCA; ERA-Net Transcan, Validation of biomarkers for personalized cancer medicine, TRANSCALL; Health-F2-2010 grant 260791, EUROCANPLATFORM), the 'Katharina Hardt Stiftung', the 'Deutsche José Carreras Leukämie-Stiftung', the 'Madeleine Schickedanz-Kinderkrebs-Stiftung', the 'Deutsche Krebshilfe – Dr. Mildred Scheel Stiftung' (grants 108613, 102588 and 108588), the Foundation of Experimental Biomedicine in Zurich, the Max Planck Society, and the 'Verein für krebskranke Kinder Hannover e.V.'. We thank A. Dehos, B. Grosche, T. Jung, W. Weiss and G. Ziegelberger, German Federal Office for Radiation Protection, as well as B. Heinzow, State Office for Social Services of Schleswig-Holstein, and A. Böttger, German Federal Ministry for the Environment, Nature Conservation, Building and Nuclear Safety for their support and critical discussions. We are grateful for the excellent technical assistance offered by the sequencing team of the Department of Vertebrate Genomics of the Max Planck Institute for Molecular Genetics (Berlin) and by the team of the Genomics Core facility of the European Molecular Biology Laboratory. We thank K. Alemazkour for excellent technical assistance regarding whole exome sequencing at the Department of Pediatric Oncology, Hematology and Clinical Immunology (Düsseldorf, Germany). We thank N. Forgo, Institute for Legal Informatics, Leibniz University Hannover, and H.-D. Tröger, Hannover Medical School, for legal and ethical counselling.

Author information

Author notes

    • Ute Fischer
    • , Michael Forster
    • , Anna Rinaldi
    • , Thomas Risch
    • , Stéphanie Sungalee
    •  & Hans-Jörg Warnatz

    These authors contributed equally to this work.

    • Arndt Borkhardt
    • , Jean-Pierre Bourquin
    • , Andre Franke
    • , Jan O Korbel
    • , Martin Stanulla
    •  & Marie-Laure Yaspo

    These authors jointly supervised this work.

Affiliations

  1. Clinic for Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.

    • Ute Fischer
    • , Michael Gombert
    • , Sebastian Ginzel
    • , Kebria Hezaveh
    • , Jessica I Höll
    • , Peter Husemann
    • , Daniel Schäfer
    • , Langhui Zhang
    •  & Arndt Borkhardt
  2. Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.

    • Michael Forster
    • , Nandini Badarinarayan
    • , Eva Ellinghaus
    • , Georg Hemmrich-Stanisak
    • , Priyadarshini Kachroo
    • , Britt S Petersen
    • , Philip Rosenstiel
    • , Stefan Schreiber
    • , Björn Stade
    •  & Andre Franke
  3. Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.

    • Anna Rinaldi
    • , Beat Bornhauser
    • , Joelle Tchinda
    • , Dardane Dakaj
    • , Sabrina Eugster
    • , Viktoras Frismantas
    • , Blerim Marovca
    • , Felix Niggli
    •  & Jean-Pierre Bourquin
  4. Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.

    • Thomas Risch
    • , Hans-Jörg Warnatz
    • , Marc Sultan
    • , Catherine L Worth
    • , Vyacheslav Amstislavskiy
    • , Meryem Ralser
    • , Hans Lehrach
    •  & Marie-Laure Yaspo
  5. European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.

    • Stéphanie Sungalee
    • , Adrian M Stütz
    • , Benjamin Raeder
    • , Thomas Zichner
    •  & Jan O Korbel
  6. Department of Algorithmic Bioinformatics, Heinrich Heine University, Düsseldorf, Germany.

    • Christina Kratsch
    •  & Alice C McHardy
  7. Department of Pediatric Hemato-Immunology, Hôpital Robert Debré and Paris Diderot University, Paris, France.

    • André Baruchel
  8. Department of Pediatrics, Christian Albrechts University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.

    • Thies Bartram
    • , Gunnar Cario
    •  & Martin Schrappe
  9. Department of Pediatrics, Laboratory of Pediatric Hematology/Oncology, University of Padova, Padova, Italy.

    • Giuseppe Basso
    •  & Geertruy te Kronnie
  10. Department of Pediatrics, Acy`badem University Medical School, Atas¸ehir, Istanbul, Turkey.

    • Cengiz Canpolat
  11. Department of Genetics, Hôpital Robert Debré and Paris Diderot University, Paris, France.

    • Hélène Cavé
  12. Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland.

    • Mauro Delorenzi
  13. Swiss Institute for Bioinformatics (SIB), Lausanne, Switzerland.

    • Mauro Delorenzi
    •  & Maria Pamela Dobay
  14. Pediatric Hematology and Oncology, Charité University Hospital, Berlin, Germany.

    • Cornelia Eckert
  15. Department of Computer Science, Bonn Rhine Sieg University of Applied Sciences, Sankt Augustin, Germany.

    • Sebastian Ginzel
    •  & Ralf Thiele
  16. Children's Cancer Research Institute, Vienna, Austria.

    • Oskar A Haas
    •  & Renate Panzer-Grümayer
  17. Northern Institute of Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.

    • Olaf Heidenreich
    •  & Anthony V Moorman
  18. Federal Office for Radiation Protection, Oberschleissheim, Germany.

    • Sabine Hornhardt
  19. Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.

    • Christian P Kratz
    • , Marketa Zaliova
    • , Martin Zimmermann
    •  & Martin Stanulla
  20. Alacris Theranostics GmbH, Berlin, Germany.

    • Moritz Schütte
    •  & Hans Lehrach
  21. Universitäts-Kinderspital beider Basel (UKBB), Basel, Switzerland.

    • Nicolas von der Weid
  22. Sheffield Children's Hospital, Sheffield, United Kingdom.

    • Ajay Vora
  23. Childhood Leukaemia Investigation Prague (CLIP), Department of Pediatric Hematology/Oncology, Second Faculty of Medicine, Charles University Prague, Prague, Czech Republic.

    • Marketa Zaliova
  24. Department of Hematology, Union Hospital, Fujian Medical University, Fuzhou, China.

    • Langhui Zhang
  25. Dahlem Centre for Genome Research and Medical Systems Biology, Berlin, Germany.

    • Hans Lehrach

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Contributions

A. Borkhardt, A.F., J.O.K., J.-P.B., M.-L.Y. and M. Stanulla jointly designed the project. A. Baruchel, A.V., A.V.M., C.C., C.P.K., F.N., G.B., G.C., G.t.K., H.C., M. Schrappe, M. Stanulla, N.v.d.W., O.A.H., C.E. and R.P.-G. provided samples or clinical data. A. Borkhardt, A.C.M., A.F., A.V., C.E., G.H.-S., H.L., J.-P.B., J.O.K., J.T., M.D., M.F., M.-L.Y., M.P.D., M. Schrappe, M. Stanulla, M. Zimmermann, O.A.H., P.R. and T.Z. contributed reagents, materials or analysis tools. A.M.S., B.B., B.M., C.E., C.L.W., H.-J.W., J.I.H., J.-P.B., M.F., M.G., S. Sungalee and U.F. designed experiments. A.M.S., A.R., B.B., B.R., B.S., B.S.P., C.E., C.K., C.L.W., D.D., D.S., H.-J.W., J.T., K.H., L.Z., M.G., M.R., M. Zaliova, M. Sultan, P.K., S.E., S. Sungalee, T.B., U.F. and V.F. performed experiments. A.R., B.S., B.S.P., C.E., C.K., C.L.W., D.S., E.E., J.I.H., H.-J.W., M.G., M.P.D., M.F., N.B., S.G., G.H.-S., P.H., P.K., M.-L.Y., M.R., M. Stanulla, M. Schütte, M. Zaliova, S. Sungalee, T.R., U.F. and V.A. analyzed data. A. Borkhardt, A.C.M., A.F., B.B., H.L., J.-P.B., J.O.K., M.D., M.F., M.-L.Y., M. Stanulla, O.H., R.T. and S. Schreiber, U.F. supervised research. A.R., C.L.W., D.S., H.-J.W., M.F., M.P.D., M. Stanulla, P.K., S. Sungalee, T.R. and U.F. prepared tables and figures. J.-P.B., M. Stanulla and M.-L.Y. wrote the manuscript. A. Borkhardt, A.F., A.R., A.V.M., H.-J.W., J.O.K., M.F., M.P.D., O.H., S.H., S. Sungalee, T.R. and U.F. contributed to the writing of the manuscript. All authors critically reviewed the manuscript for its content.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jean-Pierre Bourquin or Martin Stanulla.

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    Supplementary Figures 1–13 and Supplementary Tables 1–4 and 8.

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    Supplementary Tables 5–7 and 9–27

    Supplementary Tables 5–7 and 9–27.

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DOI

https://doi.org/10.1038/ng.3362

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