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Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets.
Hoell, Jessica I Ginzel, Sebastian Kuhlen, Michaela Kloetgen, Andreas Gombert, Michael Fischer, Ute Hein, Daniel Demir, Salih Stanulla, Martin Schrappe, Martin
Hoell, Jessica I
Ginzel, Sebastian
Kuhlen, Michaela
Kloetgen, Andreas
Gombert, Michael
Fischer, Ute
Hein, Daniel
Demir, Salih
Stanulla, Martin
Schrappe, Martin
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2019-10-22
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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.
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Blood Adv. 2019 Oct 22;3(20):3143-3156. doi: 10.1182/bloodadvances.2019000051.
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en
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2473-9537
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Attribution-NonCommercial-ShareAlike 4.0 International