Hoell, J.I.J.I.HoellGinzel, SebastianSebastianGinzelKuhlen, M.M.KuhlenKloetgen, A.A.KloetgenGombert, M.M.GombertFischer, U.U.FischerHein, D.D.HeinDemir, S.S.DemirStanulla, M.M.StanullaSchrappe, M.M.SchrappeStadt, U. zurU. zurStadtBader, P.P.BaderBabor, F.F.BaborSchuster, F.F.SchusterStrahm, B.B.StrahmAlten, J.J.AltenMoericke, A.A.MoerickeEscherich, G.G.EscherichStackelberg, A. vonA. vonStackelbergThiele, RalfRalfThieleMcHardy, A.C.A.C.McHardyPeters, C.C.PetersBornhauser, B.B.BornhauserBourquin, J.-P.J.-P.BourquinKrause, S.S.KrauseEnczmann, J.J.EnczmannMeyer, L.H.L.H.MeyerEckert, C.C.EckertBorkhardt, A.A.BorkhardtMeisel, R.R.Meisel2022-03-062022-03-062019https://publica.fraunhofer.de/handle/publica/26745410.1182/bloodadvances.2019000051Survival 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.en005006629journal article