X-linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed/refractory ALL.
PDX
XIAP
relapsed/refractory acute lymphoblastic leukemia
smac mimetics
therapeutic target
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
11 01 2023
11 01 2023
Historique:
revised:
23
10
2022
received:
14
05
2021
accepted:
28
10
2022
pubmed:
24
11
2022
medline:
13
1
2023
entrez:
23
11
2022
Statut:
ppublish
Résumé
Acute lymphoblastic leukemia (ALL) represents the most frequent malignancy in children, and relapse/refractory (r/r) disease is difficult to treat, both in children and adults. In search for novel treatment options against r/r ALL, we studied inhibitor of apoptosis proteins (IAP) and Smac mimetics (SM). SM-sensitized r/r ALL cells towards conventional chemotherapy, even upon resistance against SM alone. The combination of SM and chemotherapy-induced cell death via caspases and PARP, but independent from cIAP-1/2, RIPK1, TNFα or NF-κB. Instead, XIAP was identified to mediate SM effects. Molecular manipulation of XIAP in vivo using microRNA-30 flanked shRNA expression in cell lines and patient-derived xenograft (PDX) models of r/r ALL mimicked SM effects and intermediate XIAP knockdown-sensitized r/r ALL cells towards chemotherapy-induced apoptosis. Interestingly, upon strong XIAP knockdown, PDX r/r ALL cells were outcompeted in vivo, even in the absence of chemotherapy. Our results indicate a yet unknown essential function of XIAP in r/r ALL and reveal XIAP as a promising therapeutic target for r/r ALL.
Identifiants
pubmed: 36416169
doi: 10.15252/emmm.202114557
pmc: PMC9832863
doi:
Substances chimiques
Antineoplastic Agents
0
Caspases
EC 3.4.22.-
Inhibitor of Apoptosis Proteins
0
Mitochondrial Proteins
0
X-Linked Inhibitor of Apoptosis Protein
0
Banques de données
GEO
['GSE184011', 'GSE66006', 'GSE78132', 'GSE37642']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e14557Informations de copyright
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.
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