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Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets
- Source :
- Hoell, Jessica I; Ginzel, Sebastian; Kuhlen, Michaela; Kloetgen, Andreas; Gombert, Michael; Fischer, Ute; Hein, Daniel; Demir, Salih; Stanulla, Martin; Schrappe, Martin; Zur Stadt, Udo; Bader, Peter; Babor, Florian; Schuster, Friedhelm; Strahm, Brigitte; Alten, Julia; Moericke, Anja; Escherich, Gabriele; von Stackelberg, Arend; Thiele, Ralf; McHardy, Alice C; Peters, Christina; Bornhauser, Beat; Bourquin, Jean-Pierre; Krause, Stefan; Enczmann, Juergen; Meyer, Lüder Hinrich; Eckert, Cornelia; Borkhardt, Arndt; Meisel, Roland (2019). Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets. Blood Advances, 3(20):3143-3156.
- Publication Year :
- 2019
-
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.
Details
- Database :
- OAIster
- Journal :
- Hoell, Jessica I; Ginzel, Sebastian; Kuhlen, Michaela; Kloetgen, Andreas; Gombert, Michael; Fischer, Ute; Hein, Daniel; Demir, Salih; Stanulla, Martin; Schrappe, Martin; Zur Stadt, Udo; Bader, Peter; Babor, Florian; Schuster, Friedhelm; Strahm, Brigitte; Alten, Julia; Moericke, Anja; Escherich, Gabriele; von Stackelberg, Arend; Thiele, Ralf; McHardy, Alice C; Peters, Christina; Bornhauser, Beat; Bourquin, Jean-Pierre; Krause, Stefan; Enczmann, Juergen; Meyer, Lüder Hinrich; Eckert, Cornelia; Borkhardt, Arndt; Meisel, Roland (2019). Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets. Blood Advances, 3(20):3143-3156.
- Notes :
- application/pdf, info:doi/10.5167/uzh-177431, English
- Publication Type :
- Electronic Resource
- Accession number :
- edsoai.on1416176776
- Document Type :
- Electronic Resource