Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets.
Biomarkers, Tumor
Child
Child, Preschool
Clonal Evolution
/ genetics
Computational Biology
/ methods
DNA Repair
Female
Hematopoietic Stem Cell Transplantation
/ methods
Humans
Immunophenotyping
Infant
Male
Mutation
Polymorphism, Single Nucleotide
Precursor Cell Lymphoblastic Leukemia-Lymphoma
/ etiology
Recurrence
Selection, Genetic
Transplantation, Homologous
Tumor Suppressor Protein p53
/ genetics
Journal
Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425
Informations de publication
Date de publication:
22 10 2019
22 10 2019
Historique:
received:
19
02
2019
accepted:
08
07
2019
entrez:
25
10
2019
pubmed:
28
10
2019
medline:
18
8
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31648313
pii: 375124
doi: 10.1182/bloodadvances.2019000051
pmc: PMC6849953
doi:
Substances chimiques
Biomarkers, Tumor
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
Types de publication
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3143-3156Informations de copyright
© 2019 by The American Society of Hematology.
Références
Bone Marrow Transplant. 2012 Oct;47(10):1307-11
pubmed: 22367344
N Engl J Med. 2018 Feb 1;378(5):439-448
pubmed: 29385370
Blood. 2015 Jan 22;125(4):600-5
pubmed: 25499761
Nat Genet. 2013 Mar;45(3):290-4
pubmed: 23377183
Bone Marrow Transplant. 2013 May;48(5):661-5
pubmed: 23128573
Cold Spring Harb Perspect Med. 2017 Mar 1;7(3):null
pubmed: 28003275
N Engl J Med. 2014 Oct 16;371(16):1507-17
pubmed: 25317870
Nat Biotechnol. 2013 Mar;31(3):213-9
pubmed: 23396013
Science. 2008 Nov 28;322(5906):1377-80
pubmed: 19039135
Bioinformatics. 2010 Mar 1;26(5):589-95
pubmed: 20080505
N Engl J Med. 2015 Jun 25;372(26):2509-20
pubmed: 26028255
Klin Padiatr. 2014 Nov;226(6-7):357-61
pubmed: 25431869
J Clin Oncol. 2010 May 10;28(14):2339-47
pubmed: 20385996
Leukemia. 2018 Mar;32(3):850-854
pubmed: 29263439
Haematologica. 2017 Jul;102(7):e249-e252
pubmed: 28360149
Cancer. 2016 Jun 15;122(12):1871-9
pubmed: 26990290
Nat Commun. 2015 Mar 19;6:6604
pubmed: 25790293
Cancer Res. 2017 Jan 15;77(2):390-400
pubmed: 27872090
Nat Genet. 2017 Aug;49(8):1211-1218
pubmed: 28671688
J Clin Oncol. 2013 Jul 20;31(21):2736-42
pubmed: 23775972
Br J Cancer. 2017 Jul 11;117(2):256-265
pubmed: 28557976
Nature. 2007 Apr 12;446(7137):758-64
pubmed: 17344859
J Clin Oncol. 2011 Aug 10;29(23):3185-93
pubmed: 21747090
N Engl J Med. 2016 Aug 25;375(8):740-53
pubmed: 27292104
BMC Cancer. 2010 Aug 02;10:400
pubmed: 20678203
Nature. 2018 Jan 25;553(7689):511-514
pubmed: 29342136
Nature. 2018 Mar 15;555(7696):371-376
pubmed: 29489755
Nat Genet. 2011 May;43(5):491-8
pubmed: 21478889
Nat Genet. 2015 Sep;47(9):1020-1029
pubmed: 26214592
J Clin Oncol. 2015 Sep 20;33(27):2938-48
pubmed: 26304874
Eur J Cancer. 2016 Sep;65:91-101
pubmed: 27479119
Oncotarget. 2016 Jan 19;7(3):2696-708
pubmed: 26527318
Exp Neurol. 2013 Mar;241:13-24
pubmed: 23219885
Nat Genet. 2015 Jun;47(6):672-6
pubmed: 25961940
Bioinformatics. 2010 Aug 15;26(16):2069-70
pubmed: 20562413
Nature. 2018 Mar 15;555(7696):321-327
pubmed: 29489754
Nat Methods. 2010 Apr;7(4):248-9
pubmed: 20354512
Br J Haematol. 2018 Jan;180(1):82-89
pubmed: 29193007
Haematologica. 2018 Apr;103(4):e147-e150
pubmed: 29419436
Leuk Res. 2015 Sep;39(9):990-1001
pubmed: 26189108
Nature. 2013 Aug 22;500(7463):415-21
pubmed: 23945592
Haematologica. 2014 Jul;99(7):1212-9
pubmed: 24727818
Genome Res. 2012 Mar;22(3):568-76
pubmed: 22300766
Haematologica. 2019 May 9;:null
pubmed: 31073076
J Clin Oncol. 2018 Feb 20;36(6):591-599
pubmed: 29300620
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Oncogene. 2010 Jul 29;29(30):4245-52
pubmed: 20498645
Front Oncol. 2016 Feb 03;6:21
pubmed: 26870698
J Clin Oncol. 2012 Oct 10;30(29):3633-9
pubmed: 22965953
Blood. 2014 Nov 27;124(23):3420-30
pubmed: 25253770
Haematologica. 2015 Nov;100(11):1442-50
pubmed: 26294725
Nat Med. 2013 Mar;19(3):368-71
pubmed: 23377281
J Clin Oncol. 2015 Apr 10;33(11):1265-74
pubmed: 25753432
N Engl J Med. 2018 Dec 13;379(24):2330-2341
pubmed: 30380364
Proc Natl Acad Sci U S A. 2016 Oct 4;113(40):11306-11311
pubmed: 27655895
Nat Protoc. 2009;4(7):1073-81
pubmed: 19561590
Blood Cancer J. 2016 Jul 15;6(7):e447
pubmed: 27421096