TY - JOUR U1 - Zeitschriftenartikel, wissenschaftlich - begutachtet (reviewed) A1 - Hoell, Jessica I. A1 - Ginzel, Sebastian A1 - Kuhlen, Michaela A1 - Kloetgen, Andreas A1 - Gombert, Michael A1 - Fischer, Ute A1 - Hein, Daniel A1 - Demir, Salih A1 - Stanulla, Martin A1 - Schrappe, Martin A1 - Zur Stadt, Udo A1 - Bader, Peter A1 - Babor, Florian A1 - Schuster, Friedhelm A1 - Strahm, Brigitte A1 - Alten, Julia A1 - Moericke, Anja A1 - Escherich, Gabriele A1 - von Stackelberg, Arend A1 - Thiele, Ralf A1 - McHardy, Alice C. A1 - Peters, Christina A1 - Bornhauser, Beat A1 - Bourquin, Jean-Pierre A1 - Krause, Stefan A1 - Enczmann, Juergen A1 - Meyer, Lüder Hinrich A1 - Eckert, Cornelia A1 - Borkhardt, Arndt A1 - Meisel, Roland T1 - Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets JF - Blood Advances N2 - 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. KW - acute KW - leukemia KW - mutation KW - genetics KW - childhood KW - genes KW - lymphocytic KW - allopurinol SN - 2473-9529 SS - 2473-9529 U6 - https://doi.org/10.1182/bloodadvances.2019000051 DO - https://doi.org/10.1182/bloodadvances.2019000051 PM - 31648313 VL - 3 IS - 20 SP - 3143 EP - 3156 PB - American Society of Hematology ER -