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Experimental Hematology and Oncology

, 2:4

First Online: 19 February 2013Received: 05 February 2013Accepted: 05 February 2013DOI: 10.1186-2162-3619-2-4

Cite this article as: Boukhiar, MA., Roger, C., Tran, J. et al. Exp Hematol Oncol 2013 2: 4. doi:10.1186-2162-3619-2-4

Abstract

BackgroundWe 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.

MethodsPrimary 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.

ResultsWe 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.

ConclusionsThis 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.

KeywordsMantle cell lymphoma LYN BCR EGR-1 Dasatinib AbbreviationsMCLMantle cell lymphoma

SFKSrc family kinase

BCRB-cell receptor

JNKc-JUN NH2-terminal kinase

EGR-1Early growth response gene-1

IGHVImmunoglobulin heavy chain variable-region

MAPKMitogen-activated protein kinases

ERKExtracellular signal-regulated kinase

CLLChronic lymphocytic leukemia

DLBCLDiffuse large B cell lymphoma

PBMCPeripheral blood mononuclear cells

TAK1Transforming growth factor-β activated kinase-1

ITAMImmunoreceptor tyrosine-based activation motif

SYKSpleen tyrosine kinase

MYCMyelocytomatosis

SH2Src-homology 2

PLCPhospholipase C

PKCProtein kinase C

ILInterleukin

STAT3Signal transducer and activator of transcription 3

Electronic supplementary materialThe online version of this article doi:10.1186-2162-3619-2-4 contains supplementary material, which is available to authorized users.

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Autor: Mohand-Akli Boukhiar - Claudine Roger - Julie Tran - Remy Gressin - Antoine Martin - Florence Ajchenbaum-Cymbalista - Nadine

Fuente: https://link.springer.com/







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