Inhibition of BCR Signaling Using the Syk Inhibitor TAK-659 Prevents Stroma-Mediated Signaling in Chronic Lymphocytic Leukemia Cells
| Autor: | Purroy, Noelia, Carabia, Júlia, Abrisqueta, Pau, Egia-Mendikute, Leire, Aguiló, Meritxell, Carpio Segura, Cecilia del Carmen, Palacio, Carles, Crespo, Marta, Bosch José, Francesc Xavier, Universitat Autònoma de Barcelona |
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0301 basic medicine
Stromal cell Microenvironment Cell Survival Chronic lymphocytic leukemia Receptors Antigen B-Cell Syk Apoptosis Immunophenotyping 03 medical and health sciences Cell Movement Cell Line Tumor hemic and lymphatic diseases Tumor Microenvironment medicine Humans Syk Kinase TAK-659 Protein Kinase Inhibitors Cell Proliferation BCR inhibitor CD40 biology business.industry Chemotaxis breakpoint cluster region medicine.disease microenvironment Burkitt Lymphoma Leukemia Lymphocytic Chronic B-Cell Coculture Techniques Pyrrolidinones Leukemia Pyrimidines 030104 developmental biology Oncology Drug Resistance Neoplasm biology.protein Cancer research Stromal Cells business Tyrosine kinase Biomarkers CLL Research Paper Signal Transduction |
| Zdroj: | Recercat: Dipósit de la Recerca de Catalunya Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona Repositorio Abierto de la UdL Universitad de Lleida Scopus-Elsevier Recercat. Dipósit de la Recerca de Catalunya instname Oncotarget |
| Popis: | // Noelia Purroy 1, * , Julia Carabia 1, * , Pau Abrisqueta 1 , Leire Egia 1 , Meritxell Aguilo 1 , Cecilia Carpio 1 , Carles Palacio 1 , Marta Crespo 1, * , Francesc Bosch 1, * 1 Laboratory of Experimental Hematology, Department of Hematology, Vall d’Hebron University Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain * These authors contributed equally to this work Correspondence to: Marta Crespo, email: macrespo@vhebron.net Keywords: CLL, Syk, microenvironment, TAK-659, BCR inhibitor Received: May 18, 2016 Accepted: November 18, 2016 Published: November 24, 2016 ABSTRACT Proliferation and survival of chronic lymphocytic leukemia (CLL) cells depend on microenvironmental signals coming from lymphoid organs. One of the key players involved in the crosstalk between CLL cells and the microenvironment is the B-cell receptor (BCR). Syk protein, a tyrosine kinase essential for BCR signaling, is therefore a rational candidate for targeted therapy in CLL. Against this background, we tested the efficacy of the highly specific Syk inhibitor TAK-659 in suppressing the favorable signaling derived from the microenvironment. To ex vivo mimic the microenvironment found in the proliferation centers, we co-cultured primary CLL cells with BM stromal cells (BMSC), CD40L and CpG ODN along with BCR stimulation. In this setting, TAK-659 inhibited the microenvironment-induced activation of Syk and downstream signaling molecules, without inhibiting the protein homologue ZAP-70 in T cells. Importantly, the pro-survival, proliferative, chemoresistant and activation effects promoted by the microenvironment were abrogated by TAK-659, which furthermore blocked CLL cell migration toward BMSC, CXCL12, and CXCL13. Combination of TAK-659 with other BCR inhibitors showed synergistic effect in inducing apoptosis, and the sequential addition of TAK-659 in ibrutinib-treated CLL cells induced significantly higher cytotoxicity. These findings provide a strong rationale for the clinical development of TAK-659 in CLL. |
| Databáze: | OpenAIRE |
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