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

  • 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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Metadaten
Document Type:Article
Language:English
Author: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
Parent Title (English):Blood Advances
Volume:3
Issue:20
First Page:3143
Last Page:3156
ISSN:2473-9529
DOI:https://doi.org/10.1182/bloodadvances.2019000051
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=31648313
Publisher:American Society of Hematology
Date of first publication:2019/10/22
Tag:acute; allopurinol; childhood; genes; genetics; leukemia; lymphocytic; mutation
Departments, institutes and facilities:Fachbereich Informatik
Institut für funktionale Gen-Analytik (IfGA)
Dewey Decimal Classification (DDC):5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 576 Genetik und Evolution
Entry in this database:2019/10/25