Inhibition of BCR signaling using the Syk inhibitor TAK-659 prevents stroma-mediated signaling in chronic lymphocytic leukemia cells
Purroy i Zuriguel, Noèlia (Hospital Universitari Vall d'Hebron)
Carabia, Júlia (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Abrisqueta, Pau (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Egia-Mendikute, Leire (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Aguiló, Meritxell (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Carpio Segura, Cecilia del Carmen (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Palacio-García, Carles (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Crespo Maull, Marta (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Bosch Albareda, Francesc 1947- (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Universitat Autònoma de Barcelona

Data:	2016
Resum:	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.
Ajuts:	Instituto de Salud Carlos III PI11-00792 Instituto de Salud Carlos III PI14-00055 Instituto de Salud Carlos III PI13-00279 Ministerio de Economía y Competitividad RYC-2012-12018
Nota:	Altres ajuts: This work was cofinanced by the European Regional Development Fund (ERDF) and Asociación Española Contra el Cáncer (AECC, M.C). N.P. is a recipient of a PhD fellowship granted by Institut de Recerca Vall d'Hebron. C.C. is supported by a grant from Sociedad Española de Hematología y Hemoterapia (SEHH).
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	CLL ; Syk ; Microenvironment ; TAK-659 ; BCR inhibitor
Publicat a:	Oncotarget, Vol. 8 (november 2016) , p. 742-756, ISSN 1949-2553

DOI: 10.18632/oncotarget.13557
PMID: 27888629

15 p, 4.6 MB

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