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Blood Adv. 2019 Oct 22;3(20):3143-3156. doi: 10.1182/bloodadvances.2019000051.

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

Author information

1
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
2
German Consortium for Translational Cancer Research (DKTK), Partner site Essen/Düsseldorf, Heidelberg, Germany.
3
Department of Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany.
4
Department of Computer Science, Bonn-Rhine-Sieg University of Applied Sciences, Sankt-Augustin, Germany.
5
Fraunhofer Institut für Intelligente Analyse und Informationssysteme, Schloss Birlinghoven, St. Augustin, Germany.
6
Computational Biology of Infection Research, Helmholtz Center for Infection Research, Braunschweig, Germany.
7
Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
8
International Graduate School of Molecular Medicine, Ulm University, Ulm, Germany.
9
Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
10
Department of Pediatrics, University Medical Center Schleswig-Holstein, Kiel Campus, Kiel, Germany.
11
Center for Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
12
University Hospital for Children and Adolescents, Frankfurt am Main, Germany.
13
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.
14
Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
15
Pediatric Hematology and Oncology, Charité University Hospital, Berlin, Germany.
16
St. Anna Children's Hospital, Vienna, Austria.
17
Department of Pediatric Oncology and Children's Research Centre, University Children's Hospital Zürich, Zürich, Switzerland.
18
Institute for Transplantation Diagnostics and Cell Therapeutics, University Hospital of Düsseldorf, Düsseldorf, Germany; and.
19
German Cancer Research Center, Heidelberg, Germany.

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.

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