title: Targeting early B-cell receptor signaling induces apoptosis in leukemic mantle cell lymphoma.
abstract: BACKGROUND
  We previously showed that B-cell receptor (BCR) signaling pathways are important for in vitro survival of mantle cell lymphoma (MCL) cells. To further identify early BCR-activated signaling pathways involved in MCL cell survival, we focused our study on BCR-proximal kinases such as LYN whose dysregulations could contribute to the aggressive course of MCL.
  
  
  METHODS
  Primary MCL cells were isolated from 14 leukemic patients. Early BCR-induced genes were identified by qRT-PCR array. The basal and BCR-induced phosphorylation of LYN and JNK were evaluated by immunoblottting. Cell survival signals were evaluated by apoptosis using flow cytometry.
  
  
  RESULTS
  We showed that LYN was constitutively phosphorylated in MCL cell lines and in 9/10 leukemic MCL cases. Treatment with dasatinib or with a specific inhibitor of Src kinases such as PP2 suppressed constitutive LYN activation and increased in vitro spontaneous apoptosis of primary MCL cells. BCR engagement resulted in an increase of LYN phosphorylation leading to activation of c-JUN NH2-terminal kinase (JNK) and over-expression of the early growth response gene-1 (EGR-1). Inhibition of JNK with SP600125 induced apoptosis and reduced level of basal and BCR-induced expression of EGR-1. Furthermore, decreasing EGR1 expression by siRNA reduced BCR-induced cell survival. Treatment with PP2 or with dasatinib suppressed BCR-induced LYN and JNK phosphorylation as well as EGR-1 upregulation and is associated with a decrease of cell survival in all cases analysed.
  
  
  CONCLUSIONS
  This study highlights the importance of BCR signaling in MCL cell survival and points out to the efficiency of kinase inhibitors in suppressing proximal BCR signaling events and in inducing apoptosis.
authors: INSERM, UMR U978, Adaptateur de Signalisation en Hématologie, F-93000, Bobigny, France. fanny.baran-marszak@avc.aphp.fr.
authors: Mohand-Akli
authors: MA
authors: Boukhiar
authors: Claudine
authors: C
authors: Roger
authors: Julie
authors: J
authors: Tran
authors: Remy
authors: R
authors: Gressin
authors: Antoine
authors: A
authors: Martin
authors: Florence
authors: F
authors: Ajchenbaum-Cymbalista
authors: Nadine
authors: N
authors: Varin-Blank
authors: Dominique
authors: D
authors: Ledoux
authors: Fanny
authors: F
authors: Baran-Marszak