# B-cell receptor / BTK signalling (to NF-κB)

Source: https://onco.cc/pathways/bcr-signalling/  
OnCo record `bcr-signalling` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Pathway
- Last checked: 2026-09-04
- 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.
- 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

## 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).

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/B-cell_receptor
- Wikipedia: https://en.wikipedia.org/wiki/B-cell_receptor
- Davis et al., Nature 2010: chronic active B-cell receptor signalling in diffuse large B-cell lymphoma: https://doi.org/10.1038/nature08638
- Ngo et al., Nature 2011: oncogenically active MYD88 mutations in human lymphoma: https://doi.org/10.1038/nature09671
- Treon et al., N Engl J Med 2012: MYD88 L265P somatic mutation in Waldenstrom macroglobulinaemia: https://doi.org/10.1056/NEJMoa1200710

## Connected records

- cancers: [Burkitt lymphoma](https://onco.cc/cancers/burkitt-lymphoma/), [Chronic lymphocytic leukaemia](https://onco.cc/cancers/cll/), [Chronic lymphocytic leukaemia, first treatment](https://onco.cc/cancers/cll-treatment-naive/), [Diffuse large B-cell lymphoma](https://onco.cc/cancers/dlbcl/), [Mantle cell lymphoma](https://onco.cc/cancers/mantle-cell-lymphoma/), [Multiple myeloma](https://onco.cc/cancers/multiple-myeloma/), [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/), [Primary CNS lymphoma](https://onco.cc/cancers/primary-cns-lymphoma/), [Relapsed or refractory chronic lymphocytic leukaemia](https://onco.cc/cancers/cll-relapsed/), [Waldenström macroglobulinaemia](https://onco.cc/cancers/waldenstrom/)
- targets: [BCL-2](https://onco.cc/targets/bcl2/), [BCL10](https://onco.cc/targets/bcl10/), [BTK (Bruton tyrosine kinase)](https://onco.cc/targets/btk/), [CARD11](https://onco.cc/targets/card11/), [CCND3](https://onco.cc/targets/ccnd3/), [CD79b](https://onco.cc/targets/cd79b/), [ID3](https://onco.cc/targets/id3/), [MALT1](https://onco.cc/targets/malt1/), [MYC](https://onco.cc/targets/myc-gene/), [MYD88](https://onco.cc/targets/myd88/), [PLCG2](https://onco.cc/targets/plcg2/), [PRKCB](https://onco.cc/targets/prkcb/), [RELA](https://onco.cc/targets/rela/), [SYK](https://onco.cc/targets/syk/), [TCF3](https://onco.cc/targets/tcf3/)
- drugs: [Bortezomib](https://onco.cc/drugs/bortezomib/), [Ibrutinib](https://onco.cc/drugs/ibrutinib/), [Lenalidomide](https://onco.cc/drugs/lenalidomide/), [Orelabrutinib](https://onco.cc/drugs/orelabrutinib/), [Venetoclax](https://onco.cc/drugs/venetoclax/)
- pathways: [Inflammation & NF-κB](https://onco.cc/pathways/inflammation-nfkb/), [Intrinsic apoptosis (BCL-2 family)](https://onco.cc/pathways/apoptosis-bcl2/), [The germinal centre reaction](https://onco.cc/pathways/germinal-centre-reaction/)
- terms: [BTK C481S, PLCG2 and BCL2 G101V resistance mutations](https://onco.cc/terms/btki-bcl2i-resistance-mutations/), [Cell of origin in practice: Hans against expression profiling, and what it changes](https://onco.cc/terms/lymphoma-bio-cell-of-origin-in-practice/), [LymphGen and the genetic clusters of large B-cell lymphoma](https://onco.cc/terms/lymphoma-bio-lymphgen/), [MYD88 L265P and CXCR4 mutations](https://onco.cc/terms/myd88-l265p/)
- biomarkers: [BTK resistance mutations: C481S, and L528W and T474I after the non-covalent inhibitors](https://onco.cc/biomarkers/btk-c481s/), [CD79B ITAM mutation](https://onco.cc/biomarkers/cd79b-itam-mutation/)
- trials: [A Study of BR Alone Versus in Combination With Acalabrutinib in Subjects With Previously Untreated MCL](https://onco.cc/trials/nct02972840/), [ARCHED](https://onco.cc/trials/arched/), [ENRICH](https://onco.cc/trials/enrich/), [ROSEWOOD](https://onco.cc/trials/rosewood/), [SHINE](https://onco.cc/trials/shine/)
- key papers: [Acalabrutinib plus bendamustine-rituximab in untreated mantle cell lymphoma](https://onco.cc/key-papers/paper-echo-acalabrutinib-bendamustine-rituximab-mantle-cell-jco-2025/), [Genetics and pathogenesis of diffuse large B-cell lymphoma](https://onco.cc/key-papers/paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018/), [Ibrutinib and rituximab versus immunochemotherapy in patients with previously untreated mantle cell lymphoma (ENRICH): a randomised, open-label, phase 2/3 superiority trial](https://onco.cc/key-papers/paper-enrich-ibrutinib-rituximab-mantle-cell-lancet-2025/), [Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma](https://onco.cc/key-papers/paper-shine-ibrutinib-bendamustine-rituximab-mantle-cell-nejm-2022/), [Randomized phase III trial of ibrutinib and R-CHOP in non-germinal centre B-cell diffuse large B-cell lymphoma (PHOENIX)](https://onco.cc/key-papers/paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019/), [ROSEWOOD: a phase II randomized study of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy in patients with relapsed or refractory follicular lymphoma](https://onco.cc/key-papers/paper-rosewood-zanubrutinib-obinutuzumab-follicular-jco-2023/)
- roadmaps: [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](https://onco.cc/roadmaps/lymphoma-roadmap/)

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