title: The degree of BCR and NFAT activation predicts clinical outcomes in chronic lymphocytic leukemia.
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.
authors.affiliation: INSERM U978, Université Paris 13, Adaptateurs de Signalisation en Hématologie, UFR-SMBH, 74 rue Marcel Cachin, Bobigny Cedex, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Le Roy
authors.forename: Pierre-Antoine
authors.initials: PA
authors.lastname: Deglesne
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chevallier
authors.forename: Taoufik
authors.initials: T
authors.lastname: Beitar
authors.forename: Virginie
authors.initials: V
authors.lastname: Eclache
authors.forename: Maude
authors.initials: M
authors.lastname: Quettier
authors.forename: Marouane
authors.initials: M
authors.lastname: Boubaya
authors.forename: Rémi
authors.initials: R
authors.lastname: Letestu
authors.forename: Vincent
authors.initials: V
authors.lastname: Lévy
authors.forename: Florence
authors.initials: F
authors.lastname: Ajchenbaum-Cymbalista
authors.forename: Nadine
authors.initials: N
authors.lastname: Varin-Blank
mesh_terms: D020013:Calcium Signaling; D002470:Cell Survival; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000628:therapy; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase; D015854:Up-Regulation; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D007075:Immunoglobulin M; D047908:Intracellular Signaling Peptides and Proteins; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D009842:Oligopeptides; D011947:Receptors, Antigen, B-Cell; C121611:VIVIT peptide; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D051966:Phospholipase C gamma