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dc.contributor.authorHoell, Jessica I
dc.contributor.authorGinzel, Sebastian
dc.contributor.authorKuhlen, Michaela
dc.contributor.authorKloetgen, Andreas
dc.contributor.authorGombert, Michael
dc.contributor.authorFischer, Ute
dc.contributor.authorHein, Daniel
dc.contributor.authorDemir, Salih
dc.contributor.authorStanulla, Martin
dc.contributor.authorSchrappe, Martin
dc.contributor.authorZur Stadt, Udo
dc.contributor.authorBader, Peter
dc.contributor.authorBabor, Florian
dc.contributor.authorSchuster, Friedhelm
dc.contributor.authorStrahm, Brigitte
dc.contributor.authorAlten, Julia
dc.contributor.authorMoericke, Anja
dc.contributor.authorEscherich, Gabriele
dc.contributor.authorvon Stackelberg, Arend
dc.contributor.authorThiele, Ralf
dc.contributor.authorMcHardy, Alice C
dc.contributor.authorPeters, Christina
dc.contributor.authorBornhauser, Beat
dc.contributor.authorBourquin, Jean-Pierre
dc.contributor.authorKrause, Stefan
dc.contributor.authorEnczmann, Juergen
dc.contributor.authorMeyer, Lüder Hinrich
dc.contributor.authorEckert, Cornelia
dc.contributor.authorBorkhardt, Arndt
dc.contributor.authorMeisel, Roland
dc.date.accessioned2019-11-06T14:49:29Z
dc.date.available2019-11-06T14:49:29Z
dc.date.issued2019-10-22
dc.identifier.citationBlood Adv. 2019 Oct 22;3(20):3143-3156. doi: 10.1182/bloodadvances.2019000051.en_US
dc.identifier.issn2473-9537
dc.identifier.pmid31648313
dc.identifier.doi10.1182/bloodadvances.2019000051
dc.identifier.urihttp://hdl.handle.net/10033/622006
dc.description.abstractSurvival 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.isoenen_US
dc.publisherAmerican Society of Haematologyen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titlePediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets.en_US
dc.typeArticleen_US
dc.contributor.departmentBRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany.en_US
dc.identifier.journalBlood Advancesen_US
refterms.dateFOA2019-11-06T14:49:30Z
dc.source.journaltitleBlood advances


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