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

Autor: Julie Tran, Nadine Varin-Blank, Dominique Ledoux, Claudine Roger, Florence Ajchenbaum-Cymbalista, Mohand-Akli Boukhiar, Fanny Baran-Marszak, Antoine Martin, Remy Gressin
Přispěvatelé: Adaptateurs de signalisation en hématologie (ASIH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13), Service d'hématologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie clinique, CHU Grenoble, Service d'Anatomopathologie, This work was supported by the GOELAMS group (Groupe Ouest-Est des Leucémies Aiguës et Maladies du Sang.) and by the Institut National du Cancer (INCA) for the tumor biobank. M.A.B. was supported by the Société Française d'Hématologie (SFH)., Université Paris 13 (UP13), BMC, Ed., Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Jazyk: angličtina
Předmět:
Zdroj: Experimental Hematology & Oncology
Experimental Hematology & Oncology, BMC, 2013, 2 (1), pp.4. ⟨10.1186/2162-3619-2-4⟩
Experimental Hematology & Oncology, Vol 2, Iss 1, p 4 (2013)
ISSN: 2162-3619
DOI: 10.1186/2162-3619-2-4
Popis: 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.
Databáze: OpenAIRE
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