X-linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed/refractory ALL.
EMBO Mol Med
; 15(1): e14557, 2023 01 11.
Article
de En
| MEDLINE
| ID: mdl-36416169
ABSTRACT
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.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Protéine inhibitrice de l'apoptose liée au chromosome X
/
Antinéoplasiques
Limites:
Adult
/
Child
/
Humans
Langue:
En
Journal:
EMBO Mol Med
Sujet du journal:
BIOLOGIA MOLECULAR
Année:
2023
Type de document:
Article
Pays d'affiliation:
Allemagne