X-linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed/refractory ALL

Carlet, Michela; Schmelz, Karin; Vergalli, Jenny; Herold, Tobias; Senft, Daniela; Jurinovic, Vindi; Hoffmann, Thomas; Proba, Jutta; Weichert, Nina; Junghanss, Christian; Roth, Mareike; Eschenburg, Georg; Barz, Malwine; Henze, Guenter; Eckert, Cornelia; Eggert, Angelika; Zuber, Johannes; Hundsdoerfer, Patrick und Jeremias, Irmela (2022): X-linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed/refractory ALL. In: EMBO Molecular Medicine, Bd. 15, Nr. 1, e14557

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, TNF alpha or NF-kappa B. 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1757-4676
• Sprache: Englisch