Back
Full-text
Journal article

Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets.

  • Hoell JI Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
  • Ginzel S Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
  • Kuhlen M Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
  • Kloetgen A Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
  • Gombert M Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
  • Fischer U Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
  • Hein D Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
  • Demir S Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
  • Stanulla M Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
  • Schrappe M Department of Pediatrics, University Medical Center Schleswig-Holstein, Kiel Campus, Kiel, Germany.
  • Zur Stadt U Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Bader P University Hospital for Children and Adolescents, Frankfurt am Main, Germany.
  • Babor F Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
  • Schuster F Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
  • Strahm B 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.
  • Alten J Department of Pediatrics, University Medical Center Schleswig-Holstein, Kiel Campus, Kiel, Germany.
  • Moericke A Department of Pediatrics, University Medical Center Schleswig-Holstein, Kiel Campus, Kiel, Germany.
  • Escherich G Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • von Stackelberg A Pediatric Hematology and Oncology, Charité University Hospital, Berlin, Germany.
  • Thiele R Department of Computer Science, Bonn-Rhine-Sieg University of Applied Sciences, Sankt-Augustin, Germany.
  • McHardy AC Computational Biology of Infection Research, Helmholtz Center for Infection Research, Braunschweig, Germany.
  • Peters C St. Anna Children's Hospital, Vienna, Austria.
  • Bornhauser B Department of Pediatric Oncology and Children's Research Centre, University Children's Hospital Zürich, Zürich, Switzerland.
  • Bourquin JP Department of Pediatric Oncology and Children's Research Centre, University Children's Hospital Zürich, Zürich, Switzerland.
  • Krause S Institute for Transplantation Diagnostics and Cell Therapeutics, University Hospital of Düsseldorf, Düsseldorf, Germany; and.
  • Enczmann J Institute for Transplantation Diagnostics and Cell Therapeutics, University Hospital of Düsseldorf, Düsseldorf, Germany; and.
  • Meyer LH Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
  • Eckert C German Consortium for Translational Cancer Research (DKTK), Partner site Essen/Düsseldorf, Heidelberg, Germany.
  • Borkhardt A Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
  • Meisel R Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
Show more…
  • 2019-10-25
Published in:
  • Blood advances. - 2019
Biomarkers, Tumor
Child
Child, Preschool
Clonal Evolution
Computational Biology
DNA Repair
Female
Hematopoietic Stem Cell Transplantation
Humans
Immunophenotyping
Infant
Male
Mutation
Polymorphism, Single Nucleotide
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Recurrence
Selection, Genetic
Transplantation, Homologous
Tumor Suppressor Protein p53
English 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.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/144675
Statistics
Document views: 27 File downloads:
  • Full-text: 0