Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets.
dc.contributor.author | Hoell, Jessica I | |
dc.contributor.author | Ginzel, Sebastian | |
dc.contributor.author | Kuhlen, Michaela | |
dc.contributor.author | Kloetgen, Andreas | |
dc.contributor.author | Gombert, Michael | |
dc.contributor.author | Fischer, Ute | |
dc.contributor.author | Hein, Daniel | |
dc.contributor.author | Demir, Salih | |
dc.contributor.author | Stanulla, Martin | |
dc.contributor.author | Schrappe, Martin | |
dc.contributor.author | Zur Stadt, Udo | |
dc.contributor.author | Bader, Peter | |
dc.contributor.author | Babor, Florian | |
dc.contributor.author | Schuster, Friedhelm | |
dc.contributor.author | Strahm, Brigitte | |
dc.contributor.author | Alten, Julia | |
dc.contributor.author | Moericke, Anja | |
dc.contributor.author | Escherich, Gabriele | |
dc.contributor.author | von Stackelberg, Arend | |
dc.contributor.author | Thiele, Ralf | |
dc.contributor.author | McHardy, Alice C | |
dc.contributor.author | Peters, Christina | |
dc.contributor.author | Bornhauser, Beat | |
dc.contributor.author | Bourquin, Jean-Pierre | |
dc.contributor.author | Krause, Stefan | |
dc.contributor.author | Enczmann, Juergen | |
dc.contributor.author | Meyer, Lüder Hinrich | |
dc.contributor.author | Eckert, Cornelia | |
dc.contributor.author | Borkhardt, Arndt | |
dc.contributor.author | Meisel, Roland | |
dc.date.accessioned | 2019-11-06T14:49:29Z | |
dc.date.available | 2019-11-06T14:49:29Z | |
dc.date.issued | 2019-10-22 | |
dc.identifier.citation | Blood Adv. 2019 Oct 22;3(20):3143-3156. doi: 10.1182/bloodadvances.2019000051. | en_US |
dc.identifier.issn | 2473-9537 | |
dc.identifier.pmid | 31648313 | |
dc.identifier.doi | 10.1182/bloodadvances.2019000051 | |
dc.identifier.uri | http://hdl.handle.net/10033/622006 | |
dc.description.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. | en_US |
dc.language.iso | en | en_US |
dc.publisher | American Society of Haematology | en_US |
dc.rights | Attribution-NonCommercial-ShareAlike 4.0 International | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | * |
dc.title | Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets. | en_US |
dc.type | Article | en_US |
dc.contributor.department | BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. | en_US |
dc.identifier.journal | Blood Advances | en_US |
refterms.dateFOA | 2019-11-06T14:49:30Z | |
dc.source.journaltitle | Blood advances |