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

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.

Standort
Deutsche Nationalbibliothek Frankfurt am Main
Umfang
Online-Ressource
Sprache
Englisch

Erschienen in
X‐linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed/refractory ALL ; day:23 ; month:11 ; year:2022 ; extent:23
EMBO molecular medicine / European Molecular Biology Organization ; (23.11.2022) (gesamt 23)

Urheber
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, Günter
Eckert, Cornelia
Eggert, Angelika
Zuber, Johannes
Hundsdoerfer, Patrick
Jeremias, Irmela

DOI
10.15252/emmm.202114557
URN
urn:nbn:de:101:1-2022112314190762446188
Rechteinformation
Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
Letzte Aktualisierung
15.08.2025, 07:27 MESZ

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Beteiligte

  • 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, Günter
  • Eckert, Cornelia
  • Eggert, Angelika
  • Zuber, Johannes
  • Hundsdoerfer, Patrick
  • Jeremias, Irmela

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