Inhibitors of BCR signalling interrupt the survival signal mediated by the micro-environment in mantle cell lymphoma.

摘要: Several studies provide evidences for mantle cell lymphoma (MCL) survival relying on B-cell receptor (BCR)-mediated signalling pathways, whereas the nature of this activation is unknown. Significant progress in MCL treatment achieved through therapies targeting BCR-associated kinases, i.e., Ibrutinib and Fostamatinib, inhibitors BTK SYK, respectively. Our study addresses signals emanating from BCR or tumour environment how inhibiting effectors might impact these signals. We found that was constitutively activated SYK phosphorylation highly increased sustained upon primary cells. Moreover, cells leukaemic patients secreted high amount IL-1β, IL-6, IL-8 CCL5. Activation induced (i) survival, (ii) STAT3 (iii) autocrine secretion IL-8, CCL5, IL-10, TNFα VEGF. Specific inhibition by Fostamatinib (R406) reversed protective effects decreased both basal BCR-induced cytokine secretions associated with phosphorylation. Interestingly, prevented inhibited adhesion to human bone marrow stromal (HMSCs) short- long-term co-culture. demonstrated relies CCL5 facilitate HMSC. Treatment blocked chemotactic signal thus increasing apoptosis.