CBFA2T3-GLIS2-dependent pediatric acute megakaryoblastic leukemia is driven by GLIS2 and sensitive to navitoclax.
BCL2
CBFA2T3-GLIS2
CP: Cancer
ETO2-GLIS2
Ras
acute megakaryoblastic leukemia
apoptosis
mouse model
navitoclax
pediatric cancer
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
26 09 2023
26 09 2023
Historique:
received:
09
02
2023
revised:
11
07
2023
accepted:
18
08
2023
medline:
5
10
2023
pubmed:
17
9
2023
entrez:
16
9
2023
Statut:
ppublish
Résumé
Pediatric acute megakaryoblastic leukemia (AMKL) is an aggressive blood cancer associated with poor therapeutic response and high mortality. Here we describe the development of CBFA2T3-GLIS2-driven mouse models of AMKL that recapitulate the phenotypic and transcriptional signatures of the human disease. We show that an activating Ras mutation that occurs in human AMKL increases the penetrance and decreases the latency of CBF2AT3-GLIS2-driven AMKL. CBFA2T3-GLIS2 and GLIS2 modulate similar transcriptional networks. We identify the dominant oncogenic properties of GLIS2 that trigger AMKL in cooperation with oncogenic Ras. We find that both CBFA2T3-GLIS2 and GLIS2 alter the expression of a number of BH3-only proteins, causing AMKL cell sensitivity to the BCL2 inhibitor navitoclax both in vitro and in vivo, suggesting a potential therapeutic option for pediatric patients suffering from CBFA2T3-GLIS2-driven AMKL.
Identifiants
pubmed: 37716355
pii: S2211-1247(23)01095-1
doi: 10.1016/j.celrep.2023.113084
pii:
doi:
Substances chimiques
navitoclax
XKJ5VVK2WD
Aniline Compounds
0
Sulfonamides
0
Oncogene Proteins, Fusion
0
CBFA2T3 protein, human
0
Repressor Proteins
0
CBFA2T3-GLIS2 fusion protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
113084Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.