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Carlet, M. ; Schmelz, K.* ; Vergalli, J. ; Herold, T. ; Senft, D. ; Jurinovic, V. ; Hoffmann, T.* ; Proba, J.* ; Weichert, N.* ; Junghanß, C.* ; Roth, M.* ; Eschenburg, G.* ; Barz, M.* ; Henze, G.* ; Eckert, C.* ; Eggert, A.* ; Zuber, J.* ; Hundsdoerfer, P.* ; Jeremias, I.

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

EMBO Mol. Med.:e14557 (2022)

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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.

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