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B‐cell receptor signalling and its crosstalk with other pathways in normal and malignant cells
Author(s) -
Seda Vaclav,
Mraz Marek
Publication year - 2015
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/ejh.12427
Subject(s) - idelalisib , syk , breakpoint cluster region , lyn , b cell receptor , bruton's tyrosine kinase , cancer research , chronic lymphocytic leukemia , crosstalk , b cell , biology , paracrine signalling , signal transduction , microbiology and biotechnology , ibrutinib , tyrosine kinase , leukemia , immunology , receptor , antibody , biochemistry , physics , optics
Abstract The physiology of B cells is intimately connected with the function of their B‐cell receptor ( BCR ). B‐cell lymphomas frequently (dys)regulate BCR signalling and thus take advantage of this pre‐existing pathway for B‐cell proliferation and survival. This has recently been underscored by clinical trials demonstrating that small molecules (fosfamatinib, ibrutinib, idelalisib) inhibiting BCR ‐associated kinases ( SYK , BTK , PI 3K) have an encouraging clinical effect. Here we describe the current knowledge of the specific aspects of BCR signalling in diffuse large B‐cell lymphoma ( DLBCL ), follicular lymphoma, chronic lymphocytic leukaemia ( CLL ) and normal B cells. Multiple factors can contribute to BCR pathway (dys)regulation in these malignancies and the activation of ‘chronic’ or ‘tonic’ BCR signalling. In lymphoma B cells, the balance of initiation, amplitude and duration of BCR activation can be influenced by a specific immunoglobulin structure, the expression and mutations of adaptor molecules (like GAB 1, BLNK , GRB 2, CARD 11), the activity of kinases (like LYN , SYK , PI 3K) or phosphatases (like SHIP ‐1, SHP ‐1 and PTEN ) and levels of micro RNA s. We also discuss the crosstalk of BCR with other signalling pathways ( NF ‐κB, adhesion through integrins, migration and chemokine signalling) to emphasise that the ‘ BCR inhibitors’ target multiple pathways interconnected with BCR , which might explain some of their clinical activity.