Clonal hierarchy of main molecular lesions in acute myeloid leukaemia.
Adult
Aged
Animals
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Clonal Evolution
Clone Cells
Combined Modality Therapy
Female
Genes, Neoplasm
Hematopoietic Stem Cell Transplantation
Heterografts
Humans
Leukemia, Myeloid, Acute
/ drug therapy
Leukocytes
Male
Mice
Mice, Inbred NOD
Middle Aged
Mutation
Neoplasm Proteins
/ genetics
Neoplasm Transplantation
Neoplastic Stem Cells
Nucleophosmin
Recurrence
Young Adult
acute myeloid leukaemia
clonality
mutations
patient-derived xenograft
relapse
Journal
British journal of haematology
ISSN: 1365-2141
Titre abrégé: Br J Haematol
Pays: England
ID NLM: 0372544
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
16
08
2019
accepted:
19
09
2019
pubmed:
11
12
2019
medline:
5
3
2021
entrez:
11
12
2019
Statut:
ppublish
Résumé
Genetic mutations in acute myeloid leukaemia (AML) are assumed to occur in a sequential order; however, the predominant hierarchical roles of specific mutated genes have not been fully described. In this study, we aimed to determine the clonal involvement of the most frequent AML-associated mutations. Using a targeted sequencing panel for 18 genes, we traced changes and relative clonal contribution of mutations in 52 patients. We analysed 35 pairs of diagnosis and relapse samples, 27 pairs of primary samples and corresponding patient-derived xenografts, and 34 pairs of total leukocytes and corresponding isolated primitive cells or blast populations. In both relapse and xenografts, we observed conservation of main leukaemic clones and variability was limited to subclones with late-acquired mutations. AML evolution thus mainly involved modification of subclones while the clonal background remained unchanged. NPM1 mutations were identified as the most probable leukaemia-transformation lesion, remaining conserved in contrast to high variation of accompanying subclonal FLT3 and NRAS mutations. DNMT3A mutations represented the most stable mutations forming a preleukaemic background in most samples. Mutations in genes IDH1/2, TET2, RUNX1, ASXL1 and U2AF1 were detected both as preleukaemic and as subclonal lesions, suggesting a non-specific order of acquisition.
Substances chimiques
NPM1 protein, human
0
Neoplasm Proteins
0
Npm1 protein, mouse
0
Nucleophosmin
117896-08-9
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
562-572Subventions
Organisme : Masarykova Univerzita
ID : MUNI/A/1105/2018
Organisme : Ministerstvo Zdravotnictví Ceské Republiky
Informations de copyright
© 2019 British Society for Haematology and John Wiley & Sons Ltd.
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