The degree of BCR and NFAT activation predicts clinical outcomes in chronic lymphocytic leukemia - Université Sorbonne Paris Nord Accéder directement au contenu
Article Dans Une Revue Blood Année : 2012

The degree of BCR and NFAT activation predicts clinical outcomes in chronic lymphocytic leukemia

Pierre-Antoine Deglesne
  • Fonction : Auteur
Nathalie Chevallier
  • Fonction : Auteur
Taoufik Beitar
  • Fonction : Auteur
Virginie Eclache
  • Fonction : Auteur
Maude Quettier
  • Fonction : Auteur
Marouane Boubaya
  • Fonction : Auteur
Rémi Letestu
  • Fonction : Auteur
Vincent Lévy
  • Fonction : Auteur
Florence Ajchenbaum-Cymbalista
  • Fonction : Auteur

Résumé

Abstract B-cell antigen receptor (BCR)–mediated signaling plays a critical role in chronic lymphocytic leukemia (CLL) pathogenesis and gives an in vitro survival advantage to B cells isolated from patients with unfavorable prognostic factors. In this study, we undertook to elucidate the signaling intermediates responsible for this biologic alteration. In responding cells only, in vitro BCR engagement triggers global phosphorylation of Syk, activation of phospholipase Cγ2, and intracellular calcium mobilization, reflecting competency of BCR signaling. The calcium–calcineurin-dependent transcription factor NFAT2 is up-regulated and to some extent constitutively activated in all CLL B cells. In contrast, its DNA-binding capacity is enhanced on IgM stimulation in responding cells only. NFAT inhibition using the VIVIT peptide prevents induction of CD23 target gene and IgM-induced survival, converting responding cells to unresponsive status. At the opposite, ionomycin-induced NFAT activity allows survival of nonresponding cells. These results demonstrate that the functional heterogeneity relies on variability of protein levels establishing BCR-dependent thresholds and NFAT-dependent activation. Finally, status of the BCR-NFAT pathway for each patient reveals its relevance for CLL clinical outcome and points out to BCR-NFAT intermediates as promising functional therapeutic targets.

Dates et versions

hal-03941367 , version 1 (16-01-2023)

Identifiants

Citer

Christine Le Roy, Pierre-Antoine Deglesne, Nathalie Chevallier, Taoufik Beitar, Virginie Eclache, et al.. The degree of BCR and NFAT activation predicts clinical outcomes in chronic lymphocytic leukemia. Blood, 2012, 120 (2), pp.356-365. ⟨10.1182/blood-2011-12-397158⟩. ⟨hal-03941367⟩
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