Viability and stress protection of chronic lymphoid leukemia cells involves overactivation of mitochondrial phosphoSTAT3Ser 727

Abstract : Chronic lymphoid leukemia (CLL) is characterized by the accumulation of functionally defective CD5-positive B lymphocytes. The clinical course of CLL is highly variable, ranging from a long-lasting indolent disease to an unpredictable and rapidly progressing leukemia requiring treatment. It is thus important to identify novel factors that reflect disease progression or contribute to its assessment. Here, we report on a novel STAT3-mediated pathway that characterizes CLL B cells-extended viability and oxidative stress control. We observed that leukemic but not normal B cells from CLL patients exhibit constitutive activation of an atypical form of the STAT3 signaling factor, phosphorylated on serine 727 (Ser 727) in the absence of detectable canonical tyrosine 705 (Tyr 705)-dependent activation in vivo. The Ser 727 -phosphorylated STAT3 molecule (pSTAT3Ser 727) is localized to the mitochondria and associates with complex I of the respiratory chain. This pSer 727 modification is further controlled by glutathione-dependent antioxidant pathway(s) that mediate stromal protection of the leukemic B cells and regulate their viability. Importantly, pSTAT3Ser 727 , but neither Tyr705-phosphorylated STAT3 nor total STAT3, levels correlate with prolonged in vivo CLL B cells survival. Furthermore, STAT3 activity contributes to the resistance to apoptosis of CLL, but not normal B cells, in vitro. These data reveal that mitochondrial (Mt) pSTAT3Ser 727 overactivity is part of the antioxidant defense pathway of CLL B cells that regulates their viability. Mt pSTAT3Ser 727 appears to be a newly identified cell-protective signal involved in CLL cells survival. Targeting pSTAT3Ser 727 could be a promising new therapeutic approach.
Type de document :
Article dans une revue
Cell Death and Disease , Nature Publishing Group, 2014, pp.e1451. 〈10.1038/cddis.2014.393〉
Liste complète des métadonnées

Littérature citée [41 références]  Voir  Masquer  Télécharger

http://www.hal.inserm.fr/inserm-01074546
Contributeur : Mireille Bos <>
Soumis le : mardi 14 octobre 2014 - 16:57:57
Dernière modification le : jeudi 11 janvier 2018 - 06:23:10
Document(s) archivé(s) le : vendredi 14 avril 2017 - 20:36:33

Fichiers

cddis2014393a.pdf
Fichiers éditeurs autorisés sur une archive ouverte

Identifiants

Collections

Citation

Claude Capron, Katayoun Jondeau, Luana Casetti, Valérie Jalbert, Caroline Costa, et al.. Viability and stress protection of chronic lymphoid leukemia cells involves overactivation of mitochondrial phosphoSTAT3Ser 727. Cell Death and Disease , Nature Publishing Group, 2014, pp.e1451. 〈10.1038/cddis.2014.393〉. 〈inserm-01074546〉

Partager

Métriques

Consultations de la notice

286

Téléchargements de fichiers

69