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Inhibitors of BCR signalling interrupt the survival signal mediated by the micro‐environment in mantle cell lymphoma
Author(s) -
Bernard Sophie,
Danglade Damien,
Gardano Laura,
Laguillier Christelle,
Lazarian Gregory,
Roger Claudine,
Thieblemont Catherine,
Marzec Jacek,
Gribben John,
Cymbalista Florence,
VarinBlank Nadine,
Ledoux Dominique,
BaranMarszak Fanny
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29326
Subject(s) - syk , bruton's tyrosine kinase , autocrine signalling , ibrutinib , cancer research , breakpoint cluster region , chemistry , microbiology and biotechnology , signal transduction , biology , tyrosine kinase , immunology , chronic lymphocytic leukemia , receptor , leukemia , biochemistry
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‐1β, IL‐6, IL‐8 and CCL5. Activation of the BCR induced ( i ) cell survival, ( ii ) STAT3 activation and ( iii ) increased autocrine secretion of IL‐1β, IL‐6, IL‐8, CCL5, IL‐10, TNFα 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‐1β, TNFα and CCL5 that might facilitate adhesion of MCL cells to HMSC. Treatment with Ibrutinib or Fostamatinib blocked the chemotactic signal thus increasing apoptosis.