Email updates

Keep up to date with the latest news and content from Experimental Hematology and Oncology and BioMed Central.

Open Access Research

Targeting early B-cell receptor signaling induces apoptosis in leukemic mantle cell lymphoma

Mohand-Akli Boukhiar12, Claudine Roger3, Julie Tran3, Remy Gressin567, Antoine Martin1247, Florence Ajchenbaum-Cymbalista123, Nadine Varin-Blank12, Dominique Ledoux127 and Fanny Baran-Marszak1237*

Author Affiliations

1 INSERM, UMR U978, Adaptateur de Signalisation en Hématologie, F-93000, Bobigny, France

2 Université Paris 13, Sorbonne Paris Cité, Labex INFLAMEX, F-93000, Bobigny, France

3 AP-HP, Service d’hématologie biologique, Hôpital Avicenne, F-93000, Bobigny, France

4 AP-HP, Service d’Anatomopathologie, Hôpital Avicenne, F-93000, Bobigny, France

5 INSERM, U823, Université Joseph Fourier, Institut Albert Bonniot, F-38000, Grenoble, France

6 CHU de Grenoble, Service d’hématologie clinique, F-38000, Grenoble, France

7 French GOELAMS Group, UMR U978 INSERM-Université Paris 13, UFR SMBH, 74 rue Marcel Cachin, 93000, Bobigny, France

For all author emails, please log on.

Experimental Hematology & Oncology 2013, 2:4  doi:10.1186/2162-3619-2-4

Published: 19 February 2013

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.

Keywords:
Mantle cell lymphoma; LYN; BCR; EGR-1; Dasatinib