@article{HoellGinzelKuhlenetal.2019,
  author    = {Jessica I. Hoell and Sebastian Ginzel and Michaela Kuhlen and Andreas Kloetgen and Michael Gombert and Ute Fischer and Daniel Hein and Salih Demir and Martin Stanulla and Martin Schrappe and Udo Zur Stadt and Peter Bader and Florian Babor and Friedhelm Schuster and Brigitte Strahm and Julia Alten and Anja Moericke and Gabriele Escherich and Arend von Stackelberg and Ralf Thiele and Alice C. McHardy and Christina Peters and Beat Bornhauser and Jean-Pierre Bourquin and Stefan Krause and Juergen Enczmann and L{\"u}der Hinrich Meyer and Cornelia Eckert and Arndt Borkhardt and Roland Meisel},
  title     = {Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets},
  series   = {Blood Advances},
  volume    = {3},
  number    = {20},
  publisher = {American Society of Hematology},
  issn      = {2473-9529},
  doi       = {10.1182/bloodadvances.2019000051},
  pages     = {3143 -- 3156},
  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.},
  language  = {en}
}