{"entity":{"id":"bcr-signalling","kind":"pathway","name":"B-cell receptor / BTK signalling (to NF-κB)","aka":[],"tldr":"The B-cell receptor is the survival switch of B cells. Signals from it pass through BTK to free NF-kappa-B, which keeps the cell alive. B-cell cancers hold it on; BTK inhibitors, proteasome inhibitors and lenalidomide each cut the line at a different point.","summary":"Antigen binding to the B-cell receptor activates SYK and BTK, then PLCγ2 and PKCβ, which assemble the CARD11-BCL10-MALT1 complex and activate the IKK kinases. IKK phosphorylates IκB, the protein that holds NF-κB (p65/p50) in the cytoplasm; IκB is ubiquitinated and destroyed by the proteasome, and NF-κB enters the nucleus to switch on BCL2, BCL-XL, IL-6, IL-10 and cyclin D. Toll-like receptors feed the same hub through MYD88 (MYD88 L265P in Waldenström macroglobulinaemia and ABC-type DLBCL), and BAFF and CD40 signals activate the alternative (NIK-dependent) branch, which matters in multiple myeloma. Activated B-cell DLBCL, chronic lymphocytic leukaemia, mantle cell lymphoma and Waldenström macroglobulinaemia depend on this circuit. Ibrutinib and the later BTK inhibitors (acalabrutinib, zanubrutinib, pirtobrutinib) block the receptor arm; bortezomib and carfilzomib stop the proteasome from destroying IκB; lenalidomide and its successors degrade IKZF1/3 and cut IRF4-driven NF-κB output in myeloma and ABC-DLBCL. Resistance comes from BTK C481S mutations, PLCγ2 mutations and CARD11 or MYD88 lesions downstream of BTK.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/B-cell_receptor","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/B-cell_receptor"},{"label":"Davis et al., Nature 2010: chronic active B-cell receptor signalling in diffuse large B-cell lymphoma","url":"https://doi.org/10.1038/nature08638"},{"label":"Ngo et al., Nature 2011: oncogenically active MYD88 mutations in human lymphoma","url":"https://doi.org/10.1038/nature09671"},{"label":"Treon et al., N Engl J Med 2012: MYD88 L265P somatic mutation in Waldenstrom macroglobulinaemia","url":"https://doi.org/10.1056/NEJMoa1200710"}],"tags":[],"related":[],"cancers":["dlbcl","cll","mantle-cell-lymphoma","waldenstrom","multiple-myeloma","non-hodgkin-lymphoma","primary-cns-lymphoma"],"sections":[],"technologies":[],"targets":["bcl2"],"drugs":["ibrutinib","bortezomib","lenalidomide","venetoclax"],"companies":[],"institutions":[],"pathways":["inflammation-nfkb","apoptosis-bcl2"],"terms":["lymphoma-bio-lymphgen"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Lymphoma: this is the one pathway in lymphoma where the biology picks the drug. Chronic active signalling in activated B-cell-like disease was shown functionally, by knocking down IgM, Ig-kappa, CD79A, CD79B or BTK and killing only those cells, and structurally, by the slow-diffusing receptor clusters that resemble an antigen-stimulated normal B cell; ITAM mutations of CD79B raise surface receptor and blunt the LYN feedback brake, and were present in 18% of activated B-cell-like cases (Davis 2010). The toll-like receptor arm feeds the same hub through MYD88 L265P, present in 29% of activated B-cell-like cases and in 91% of lymphoplasmacytic lymphoma (Ngo 2011, Treon 2012)."],"analogy":"A guard (IκB) holds a prisoner (NF-kappa-B) who, once free, orders the cell to survive. The B-cell receptor sends a runner (BTK) to hand the guard to the shredder (proteasome). BTK inhibitors stop the runner, proteasome inhibitors jam the shredder, and lenalidomide removes the clerks (IKZF1/3) who file the survival orders.","nodes":[{"id":"bcr","label":"B-cell receptor / antigen","x":30,"y":5},{"id":"tlr","label":"TLR → MYD88 (L265P)","x":70,"y":5},{"id":"btk","label":"SYK → BTK → PLCγ2","x":30,"y":24},{"id":"cbm","label":"CARD11 / BCL10 / MALT1","x":50,"y":42},{"id":"ikk","label":"IKK complex","x":50,"y":58},{"id":"ikb","label":"IκB (destroyed by proteasome)","x":18,"y":74},{"id":"nfkb","label":"NF-κB (p65 / p50)","x":50,"y":74},{"id":"irf4","label":"IRF4 / IKZF1-3 (lenalidomide)","x":82,"y":74},{"id":"out","label":"BCL2, IL-6, IL-10, cyclin D → survival","x":50,"y":95,"targetId":"bcl2"}],"edges":[{"from":"bcr","to":"btk","type":"activates"},{"from":"btk","to":"cbm","type":"activates"},{"from":"tlr","to":"cbm","type":"activates"},{"from":"cbm","to":"ikk","type":"activates"},{"from":"ikk","to":"ikb","type":"inhibits"},{"from":"ikb","to":"nfkb","type":"inhibits"},{"from":"nfkb","to":"out","type":"activates"},{"from":"irf4","to":"nfkb","type":"activates"},{"from":"nfkb","to":"irf4","type":"activates"}],"interventions":["Covalent BTK inhibitors ibrutinib, acalabrutinib, zanubrutinib; non-covalent pirtobrutinib after BTK C481S resistance; BTK degraders in trials","Proteasome inhibitors bortezomib, carfilzomib and ixazomib block IκB degradation in multiple myeloma and mantle cell lymphoma","Lenalidomide and the CELMoDs degrade IKZF1/3, cutting IRF4 and NF-κB output","BCL2 inhibition (venetoclax) removes the main survival gene NF-κB switches on"]},"route":"/pathways/bcr-signalling/","neighbours":{"cancer":[{"id":"burkitt-lymphoma","kind":"cancer","name":"Burkitt lymphoma","route":"/cancers/burkitt-lymphoma/"},{"id":"cll","kind":"cancer","name":"Chronic lymphocytic leukaemia","route":"/cancers/cll/"},{"id":"cll-treatment-naive","kind":"cancer","name":"Chronic lymphocytic leukaemia, first treatment","route":"/cancers/cll-treatment-naive/"},{"id":"dlbcl","kind":"cancer","name":"Diffuse large B-cell lymphoma","route":"/cancers/dlbcl/"},{"id":"mantle-cell-lymphoma","kind":"cancer","name":"Mantle cell lymphoma","route":"/cancers/mantle-cell-lymphoma/"},{"id":"multiple-myeloma","kind":"cancer","name":"Multiple myeloma","route":"/cancers/multiple-myeloma/"},{"id":"non-hodgkin-lymphoma","kind":"cancer","name":"Non-Hodgkin lymphoma (all types)","route":"/cancers/non-hodgkin-lymphoma/"},{"id":"primary-cns-lymphoma","kind":"cancer","name":"Primary CNS lymphoma","route":"/cancers/primary-cns-lymphoma/"},{"id":"cll-relapsed","kind":"cancer","name":"Relapsed or refractory chronic lymphocytic leukaemia","route":"/cancers/cll-relapsed/"},{"id":"waldenstrom","kind":"cancer","name":"Waldenström macroglobulinaemia","route":"/cancers/waldenstrom/"}],"target":[{"id":"bcl2","kind":"target","name":"BCL-2","route":"/targets/bcl2/"},{"id":"bcl10","kind":"target","name":"BCL10","route":"/targets/bcl10/"},{"id":"btk","kind":"target","name":"BTK (Bruton tyrosine kinase)","route":"/targets/btk/"},{"id":"card11","kind":"target","name":"CARD11","route":"/targets/card11/"},{"id":"ccnd3","kind":"target","name":"CCND3","route":"/targets/ccnd3/"},{"id":"cd79b","kind":"target","name":"CD79b","route":"/targets/cd79b/"},{"id":"id3","kind":"target","name":"ID3","route":"/targets/id3/"},{"id":"malt1","kind":"target","name":"MALT1","route":"/targets/malt1/"},{"id":"myc-gene","kind":"target","name":"MYC","route":"/targets/myc-gene/"},{"id":"myd88","kind":"target","name":"MYD88","route":"/targets/myd88/"},{"id":"plcg2","kind":"target","name":"PLCG2","route":"/targets/plcg2/"},{"id":"prkcb","kind":"target","name":"PRKCB","route":"/targets/prkcb/"},{"id":"rela","kind":"target","name":"RELA","route":"/targets/rela/"},{"id":"syk","kind":"target","name":"SYK","route":"/targets/syk/"},{"id":"tcf3","kind":"target","name":"TCF3","route":"/targets/tcf3/"}],"drug":[{"id":"bortezomib","kind":"drug","name":"Bortezomib","route":"/drugs/bortezomib/"},{"id":"ibrutinib","kind":"drug","name":"Ibrutinib","route":"/drugs/ibrutinib/"},{"id":"lenalidomide","kind":"drug","name":"Lenalidomide","route":"/drugs/lenalidomide/"},{"id":"orelabrutinib","kind":"drug","name":"Orelabrutinib","route":"/drugs/orelabrutinib/"},{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"}],"pathway":[{"id":"inflammation-nfkb","kind":"pathway","name":"Inflammation & NF-κB","route":"/pathways/inflammation-nfkb/"},{"id":"apoptosis-bcl2","kind":"pathway","name":"Intrinsic apoptosis (BCL-2 family)","route":"/pathways/apoptosis-bcl2/"},{"id":"germinal-centre-reaction","kind":"pathway","name":"The germinal centre reaction","route":"/pathways/germinal-centre-reaction/"}],"term":[{"id":"btki-bcl2i-resistance-mutations","kind":"term","name":"BTK C481S, PLCG2 and BCL2 G101V resistance mutations","route":"/terms/btki-bcl2i-resistance-mutations/"},{"id":"lymphoma-bio-cell-of-origin-in-practice","kind":"term","name":"Cell of origin in practice: Hans against expression profiling, and what it changes","route":"/terms/lymphoma-bio-cell-of-origin-in-practice/"},{"id":"lymphoma-bio-lymphgen","kind":"term","name":"LymphGen and the genetic clusters of large B-cell lymphoma","route":"/terms/lymphoma-bio-lymphgen/"},{"id":"myd88-l265p","kind":"term","name":"MYD88 L265P and CXCR4 mutations","route":"/terms/myd88-l265p/"}],"biomarker":[{"id":"btk-c481s","kind":"biomarker","name":"BTK resistance mutations: C481S, and L528W and T474I after the non-covalent inhibitors","route":"/biomarkers/btk-c481s/"},{"id":"cd79b-itam-mutation","kind":"biomarker","name":"CD79B ITAM mutation","route":"/biomarkers/cd79b-itam-mutation/"}],"trial":[{"id":"nct02972840","kind":"trial","name":"A Study of BR Alone Versus in Combination With Acalabrutinib in Subjects With Previously Untreated MCL","route":"/trials/nct02972840/"},{"id":"arched","kind":"trial","name":"ARCHED","route":"/trials/arched/"},{"id":"enrich","kind":"trial","name":"ENRICH","route":"/trials/enrich/"},{"id":"rosewood","kind":"trial","name":"ROSEWOOD","route":"/trials/rosewood/"},{"id":"shine","kind":"trial","name":"SHINE","route":"/trials/shine/"}],"paper":[{"id":"paper-echo-acalabrutinib-bendamustine-rituximab-mantle-cell-jco-2025","kind":"paper","name":"Acalabrutinib plus bendamustine-rituximab in untreated mantle cell lymphoma","route":"/key-papers/paper-echo-acalabrutinib-bendamustine-rituximab-mantle-cell-jco-2025/"},{"id":"paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018","kind":"paper","name":"Genetics and pathogenesis of diffuse large B-cell lymphoma","route":"/key-papers/paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018/"},{"id":"paper-enrich-ibrutinib-rituximab-mantle-cell-lancet-2025","kind":"paper","name":"Ibrutinib and rituximab versus immunochemotherapy in patients with previously untreated mantle cell lymphoma (ENRICH): a randomised, open-label, phase 2/3 superiority trial","route":"/key-papers/paper-enrich-ibrutinib-rituximab-mantle-cell-lancet-2025/"},{"id":"paper-shine-ibrutinib-bendamustine-rituximab-mantle-cell-nejm-2022","kind":"paper","name":"Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma","route":"/key-papers/paper-shine-ibrutinib-bendamustine-rituximab-mantle-cell-nejm-2022/"},{"id":"paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019","kind":"paper","name":"Randomized phase III trial of ibrutinib and R-CHOP in non-germinal centre B-cell diffuse large B-cell lymphoma (PHOENIX)","route":"/key-papers/paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019/"},{"id":"paper-rosewood-zanubrutinib-obinutuzumab-follicular-jco-2023","kind":"paper","name":"ROSEWOOD: a phase II randomized study of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy in patients with relapsed or refractory follicular lymphoma","route":"/key-papers/paper-rosewood-zanubrutinib-obinutuzumab-follicular-jco-2023/"}],"roadmap":[{"id":"lymphoma-roadmap","kind":"roadmap","name":"Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting","route":"/roadmaps/lymphoma-roadmap/"}]}}