Blood Advances (Oct 2019)
Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets
- Jessica I. Hoell,
- Sebastian Ginzel,
- Michaela Kuhlen,
- Andreas Kloetgen,
- Michael Gombert,
- Ute Fischer,
- Daniel Hein,
- Salih Demir,
- Martin Stanulla,
- Martin Schrappe,
- Udo zur Stadt,
- Peter Bader,
- Florian Babor,
- Friedhelm Schuster,
- Brigitte Strahm,
- Julia Alten,
- Anja Moericke,
- Gabriele Escherich,
- Arend von Stackelberg,
- Ralf Thiele,
- Alice C. McHardy,
- Christina Peters,
- Beat Bornhauser,
- Jean-Pierre Bourquin,
- Stefan Krause,
- Juergen Enczmann,
- Lüder Hinrich Meyer,
- Cornelia Eckert,
- Arndt Borkhardt,
- Roland Meisel
Affiliations
- Jessica I. Hoell
- Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany;; German Consortium for Translational Cancer Research (DKTK), Partner site Essen/Düsseldorf, Heidelberg, Germany;; Department of Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany;; Jessica I. Hoell, Department of Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str 40, 06120 Halle (Saale), Germany;
- Sebastian Ginzel
- Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany;; German Consortium for Translational Cancer Research (DKTK), Partner site Essen/Düsseldorf, Heidelberg, Germany;; Department of Computer Science, Bonn-Rhine-Sieg University of Applied Sciences, Sankt-Augustin, Germany;; Fraunhofer Institut für Intelligente Analyse und Informationssysteme, Schloss Birlinghoven, St. Augustin, Germany;
- Michaela Kuhlen
- Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany;; German Consortium for Translational Cancer Research (DKTK), Partner site Essen/Düsseldorf, Heidelberg, Germany;
- Andreas Kloetgen
- Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany;; German Consortium for Translational Cancer Research (DKTK), Partner site Essen/Düsseldorf, Heidelberg, Germany;; Computational Biology of Infection Research, Helmholtz Center for Infection Research, Braunschweig, Germany;
- Michael Gombert
- Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany;; German Consortium for Translational Cancer Research (DKTK), Partner site Essen/Düsseldorf, Heidelberg, Germany;
- Ute Fischer
- Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany;; German Consortium for Translational Cancer Research (DKTK), Partner site Essen/Düsseldorf, Heidelberg, Germany;
- Daniel Hein
- Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany;; German Consortium for Translational Cancer Research (DKTK), Partner site Essen/Düsseldorf, Heidelberg, Germany;
- Salih Demir
- Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany;; International Graduate School of Molecular Medicine, Ulm University, Ulm, Germany.
- Martin Stanulla
- Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany;
- Martin Schrappe
- Department of Pediatrics, University Medical Center Schleswig-Holstein, Kiel Campus, Kiel, Germany;
- Udo zur Stadt
- Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
- Peter Bader
- University Hospital for Children and Adolescents, Frankfurt am Main, Germany;
- Florian Babor
- Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany;; German Consortium for Translational Cancer Research (DKTK), Partner site Essen/Düsseldorf, Heidelberg, Germany;
- Friedhelm Schuster
- Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany;; German Consortium for Translational Cancer Research (DKTK), Partner site Essen/Düsseldorf, Heidelberg, Germany;
- Brigitte Strahm
- Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany;
- Julia Alten
- Department of Pediatrics, University Medical Center Schleswig-Holstein, Kiel Campus, Kiel, Germany;
- Anja Moericke
- Department of Pediatrics, University Medical Center Schleswig-Holstein, Kiel Campus, Kiel, Germany;
- Gabriele Escherich
- Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
- Arend von Stackelberg
- Pediatric Hematology and Oncology, Charité University Hospital, Berlin, Germany;
- Ralf Thiele
- Department of Computer Science, Bonn-Rhine-Sieg University of Applied Sciences, Sankt-Augustin, Germany;
- Alice C. McHardy
- Computational Biology of Infection Research, Helmholtz Center for Infection Research, Braunschweig, Germany;
- Christina Peters
- St. Anna Children's Hospital, Vienna, Austria;
- Beat Bornhauser
- Department of Pediatric Oncology and Children's Research Centre, University Children's Hospital Zürich, Zürich, Switzerland;
- Jean-Pierre Bourquin
- Department of Pediatric Oncology and Children's Research Centre, University Children's Hospital Zürich, Zürich, Switzerland;
- Stefan Krause
- Institute for Transplantation Diagnostics and Cell Therapeutics, University Hospital of Düsseldorf, Düsseldorf, Germany
- Juergen Enczmann
- Institute for Transplantation Diagnostics and Cell Therapeutics, University Hospital of Düsseldorf, Düsseldorf, Germany
- Lüder Hinrich Meyer
- Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany;
- Cornelia Eckert
- German Consortium for Translational Cancer Research (DKTK), Partner site Essen/Düsseldorf, Heidelberg, Germany;; Pediatric Hematology and Oncology, Charité University Hospital, Berlin, Germany;; German Cancer Research Center, Heidelberg, Germany
- Arndt Borkhardt
- Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany;; German Consortium for Translational Cancer Research (DKTK), Partner site Essen/Düsseldorf, Heidelberg, Germany;
- Roland Meisel
- Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany;; German Consortium for Translational Cancer Research (DKTK), Partner site Essen/Düsseldorf, Heidelberg, Germany;
- Journal volume & issue
-
Vol. 3,
no. 20
pp. 3143 – 3156
Abstract
Abstract: Survival of patients with pediatric acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-SCT) is mainly compromised by leukemia relapse, carrying dismal prognosis. As novel individualized therapeutic approaches are urgently needed, we performed whole-exome sequencing of leukemic blasts of 10 children with post–allo-SCT relapses with the aim of thoroughly characterizing the mutational landscape and identifying druggable mutations. We found that post–allo-SCT ALL relapses display highly diverse and mostly patient-individual genetic lesions. Moreover, mutational cluster analysis showed substantial clonal dynamics during leukemia progression from initial diagnosis to relapse after allo-SCT. Only very few alterations stayed constant over time. This dynamic clonality was exemplified by the detection of thiopurine resistance-mediating mutations in the nucleotidase NT5C2 in 3 patients' first relapses, which disappeared in the post–allo-SCT relapses on relief of selective pressure of maintenance chemotherapy. Moreover, we identified TP53 mutations in 4 of 10 patients after allo-SCT, reflecting acquired chemoresistance associated with selective pressure of prior antineoplastic treatment. Finally, in 9 of 10 children's post–allo-SCT relapse, we found alterations in genes for which targeted therapies with novel agents are readily available. We could show efficient targeting of leukemic blasts by APR-246 in 2 patients carrying TP53 mutations. Our findings shed light on the genetic basis of post–allo-SCT relapse and may pave the way for unraveling novel therapeutic strategies in this challenging situation.
