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

Several studies provide evidences for mantle cell lymphoma (MCL) cell survival relying on B-cell receptor (BCR)-mediated signalling pathways, whereas the nature of this activation is unknown. Significant progress in MCL treatment is achieved through therapies targeting BCR-associated kinases, i.e., Ibrutinib and Fostamatinib, inhibitors of BTK and SYK, respectively. Our study addresses survival signals emanating from the BCR or the tumour environment and how inhibiting BCR signalling effectors might impact these survival signals. We found that BTK was constitutively activated and that SYK phosphorylation was highly increased and sustained upon BCR activation of primary MCL cells. Moreover, MCL cells from leukaemic patients secreted high amount of IL-1, IL-6, IL-8 and CCL5. Activation of the BCR induced (i) cell survival, (ii) STAT3 activation and (iii) increased autocrine secretion of IL-1, IL-6, IL-8, CCL5, IL-10, TNF and VEGF. Specific inhibition of BTK by Ibrutinib or SYK by Fostamatinib (R406) reversed these protective effects and decreased both basal and BCR-induced autocrine cytokine secretions associated with STAT3 phosphorylation. Interestingly, targeting BTK and SYK prevented and inhibited BCR-induced MCL cell adhesion to human bone marrow stromal cells (HMSCs) in short- and long-term co-culture. We demonstrated that BCR-induced survival relies on autocrine secretion of IL-1, TNF and CCL5 that might facilitate adhesion of MCL cells to HMSC. Treatment with Ibrutinib or Fostamatinib blocked the chemotactic signal thus increasing apoptosis. What's new? While there is evidence that Mantle Cell Lymphoma (MCL) cells rely on B-cell receptor (BCR)-mediated signalling pathways for their survival, the nature of such activation remains unknown. Significant progress in MCL treatment was nonetheless achieved through therapies targeting BCR-associated kinases such as Ibrutinib and Fostamatinib. Here, the authors showed that the inhibition of SYK by Fostamatinib or BTK by Ibrutinib altered BCR-induced secretion of IL1, IL6, IL8, VEGF, TNF, and CCL5. These effectors could mediate survival of MCL cells through their homing and adhesion to bone marrow stromal cells. Moreover, Fostamatinib and Ibrutinib impaired NF-B-dependent STAT3 activation, leading to apoptosis.