BET inhibitors impair leukemic stem cell function only in defined oncogenic subgroups of acute myeloid leukaemias.
Animals
Antineoplastic Agents
/ pharmacology
Hematopoietic Stem Cell Transplantation
Humans
Leukemia, Myeloid, Acute
/ genetics
Mice
Mice, Transgenic
Mutation
Neoplasm Staging
Neoplastic Stem Cells
/ drug effects
Nucleophosmin
Oncogenes
/ genetics
Proteins
/ antagonists & inhibitors
Treatment Outcome
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Acute myeloid leukaemia
BET bromodomains
Leukemic stem cells
Long term culture
MLL partial tandem duplication
Journal
Leukemia research
ISSN: 1873-5835
Titre abrégé: Leuk Res
Pays: England
ID NLM: 7706787
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
18
09
2019
revised:
30
10
2019
accepted:
05
11
2019
pubmed:
22
11
2019
medline:
28
5
2020
entrez:
22
11
2019
Statut:
ppublish
Résumé
Bromodomain and Extra-Terminal inhibitors (BETi) such as OTX015 are active in Acute Myeloid Leukaemias (AML). Their activity on Leukemic Stem Cells (LSCs) is less documented. We interrogated the anti-LSC activity of OTX015 in a niche-like long-term culture in 26 primary AML samples and validated our findings in vivo. OTX015 impaired LSCs in AMLs harbouring Core Binding Factor or KMT2A gene fusions, NPM1 or chromatin/spliceosome genes mutations, but not in those with aneuploidy/TP53 mutations. In four patients, we dissected the transcriptomic footprint of Bet inhibition on LSCs versus blasts. Our results can instruct future clinical trials of BETi in AML.
Identifiants
pubmed: 31751766
pii: S0145-2126(19)30714-3
doi: 10.1016/j.leukres.2019.106269
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
NPM1 protein, human
0
Npm1 protein, mouse
0
Proteins
0
bromodomain and extra-terminal domain protein, human
0
Nucleophosmin
117896-08-9
Types de publication
Letter
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
106269Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.