Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
AuthorsHoell, Jessica I
Zur Stadt, Udo
von Stackelberg, Arend
McHardy, Alice C
Meyer, Lüder Hinrich
MetadataShow full item record
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.
CitationBlood Adv. 2019 Oct 22;3(20):3143-3156. doi: 10.1182/bloodadvances.2019000051.
AffiliationBRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany.
PublisherAmerican Society of Haematology
The following license files are associated with this item:
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-ShareAlike 4.0 International
- A review on allogeneic stem cell transplantation for newly diagnosed pediatric acute myeloid leukemia.
- Authors: Niewerth D, Creutzig U, Bierings MB, Kaspers GJ
- Issue date: 2010 Sep 30
- Outcome of relapse after allogeneic HSCT in children with ALL enrolled in the ALL-SCT 2003/2007 trial.
- Authors: Kuhlen M, Willasch AM, Dalle JH, Wachowiak J, Yaniv I, Ifversen M, Sedlacek P, Guengoer T, Lang P, Bader P, Sufliarska S, Balduzzi A, Strahm B, von Luettichau I, Hoell JI, Borkhardt A, Klingebiel T, Schrappe M, von Stackelberg A, Glogova E, Poetschger U, Meisel R, Peters C
- Issue date: 2018 Jan
- Prevalence of extramedullary relapses is higher after allogeneic stem cell transplantation than after chemotherapy in adult patients with acute myeloid leukemia.
- Authors: Shimizu H, Saitoh T, Hatsumi N, Takada S, Handa H, Jimbo T, Sakura T, Miyawaki S, Nojima Y
- Issue date: 2013 Nov
- Mutational analysis of disease relapse in patients allografted for acute myeloid leukemia.
- Authors: Quek L, Ferguson P, Metzner M, Ahmed I, Kennedy A, Garnett C, Jeffries S, Walter C, Piechocki K, Timbs A, Danby R, Raghavan M, Peniket A, Griffiths M, Bacon A, Ward J, Wheatley K, Vyas P, Craddock C
- Issue date: 2016 Dec 27
- High prognostic value of pre-allogeneic stem cell transplantation minimal residual disease detection by WT1 gene expression in AML transplanted in cytologic complete remission.
- Authors: Candoni A, De Marchi F, Zannier ME, Lazzarotto D, Filì C, Dubbini MV, Rabassi N, Toffoletti E, Lau BW, Fanin R
- Issue date: 2017 Dec