{"entity":{"id":"germinal-centre-reaction","kind":"pathway","name":"The germinal centre reaction","aka":["Germinal centre","Germinal center reaction","Somatic hypermutation and class switching","Affinity maturation"],"tldr":"To make a good antibody, a B cell has to deliberately damage its own DNA and keep dividing while it does. The germinal centre is where that happens, under strict time limits. Most B-cell lymphomas are cells that went through it and did not come out.","summary":"When a B cell meets an antigen it has not seen before, it enters a lymph node follicle and starts a germinal centre. There it does three dangerous things at once. It switches on activation-induced cytidine deaminase, which deliberately mutates the variable region of its own immunoglobulin genes so that a better-binding version can be selected. It cuts and rejoins the constant region to change antibody class. And it divides faster than almost any cell in the body. To survive this, BCL6 holds down the DNA damage response and the differentiation programme, polycomb repressive complex 2 keeps the exit genes methylated shut, and CREBBP and EP300 provide the acetylation that turns the programme back off at the end.\n\nAlmost every lesion in B-cell lymphoma is a failure of one of those safeguards. Translocations of BCL2 and MYC to an immunoglobulin locus are mistakes made by the recombinases that cut these genes on purpose. EZH2 gain-of-function mutations hold the polycomb mark on, so the exit never happens. CREBBP and EP300 loss leaves BCL6 acetylated less and therefore active more. The cell of origin classification of diffuse large B-cell lymphoma is a description of where in this reaction the cancer got stuck: germinal-centre-like cells are still inside it, activated B-cell-like cells are at the exit and cannot complete it.\n\nThe reaction is also why these cancers keep their normal lineage's weaknesses. A germinal-centre B cell still carries CD19, CD20, CD79b and CD22, which is why antibodies work and why they strip out the healthy B-cell compartment at the same time.","asOf":"2026-09-30","links":[{"label":"Tsujimoto et al., Science 1985: the t(14;18) translocation results from a mistake in VDJ joining","url":"https://doi.org/10.1126/science.3929382"},{"label":"Morin et al., Nat Genet 2010: somatic EZH2 Tyr641 mutations in follicular and germinal-centre diffuse large B-cell lymphoma","url":"https://doi.org/10.1038/ng.518"},{"label":"Pasqualucci et al., Nature 2011: inactivating mutations of the acetyltransferase genes CREBBP and EP300 in B-cell lymphoma","url":"https://doi.org/10.1038/nature09730"},{"label":"Alizadeh et al., Nature 2000: distinct types of diffuse large B-cell lymphoma identified by gene expression profiling","url":"https://doi.org/10.1038/35000501"}],"tags":["pathway","lymphoma"],"related":[],"cancers":["dlbcl","follicular-lymphoma","burkitt-lymphoma","non-hodgkin-lymphoma","primary-mediastinal-b-cell-lymphoma"],"sections":[],"technologies":[],"targets":["bcl6","ezh2","crebbp","ep300","bcl2","myc-gene","kmt2d"],"drugs":[],"companies":[],"institutions":[],"pathways":["epigenetic-reprogramming","apoptosis-bcl2","bcr-signalling","myc"],"terms":["lymphoma-bio-germinal-centre","cell-of-origin"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"analogy":"A proof-reading workshop where the only way to improve a design is to make random changes to the blueprint and test them. While the workshop is running, the fire alarm (p53 and the damage response) is switched off and the exit door (differentiation) is locked, because nobody must leave mid-experiment. Lymphoma is what happens when a worker jams the lock or cuts the alarm wire permanently.","nodes":[{"id":"antigen","label":"Antigen and T-cell help (CD40, IL-21)","x":50,"y":5},{"id":"bcl6","label":"BCL6 switches off the damage response","x":25,"y":26,"targetId":"bcl6"},{"id":"aid","label":"AID mutates the immunoglobulin genes","x":72,"y":26},{"id":"prc2","label":"PRC2 / EZH2 keeps the exit genes shut","x":25,"y":48,"targetId":"ezh2"},{"id":"select","label":"Selection in the light zone: better binders survive","x":72,"y":48},{"id":"hat","label":"CREBBP / EP300 acetylation releases the brake","x":50,"y":68,"targetId":"crebbp"},{"id":"exit","label":"Exit as a plasma cell or memory B cell","x":25,"y":88},{"id":"lymphoma","label":"Stuck: BCL2 and MYC translocation, EZH2 gain, CREBBP loss","x":75,"y":88,"targetId":"bcl2"}],"edges":[{"from":"antigen","to":"bcl6","type":"activates"},{"from":"antigen","to":"aid","type":"activates"},{"from":"bcl6","to":"prc2","type":"activates"},{"from":"aid","to":"select","type":"activates"},{"from":"prc2","to":"hat","type":"activates"},{"from":"select","to":"hat","type":"activates"},{"from":"hat","to":"exit","type":"activates"},{"from":"hat","to":"lymphoma","type":"inhibits"},{"from":"prc2","to":"lymphoma","type":"activates"},{"from":"bcl6","to":"exit","type":"inhibits"}],"interventions":["EZH2 inhibition (tazemetostat) in follicular lymphoma, which is the only licensed drug that acts on this reaction directly and the only one selected by a germinal-centre genotype","BCL-2 inhibition (venetoclax) against the anti-apoptotic protein the t(14;18) translocation put there","HDAC inhibition as the proposed answer to CREBBP loss, on the argument that a cell short of acetyltransferase is dependent on keeping the deacetylase in check; in trials, not approved for this indication","BCL6 degraders and inhibitors, in early trials","Every anti-CD19, anti-CD20, anti-CD79b and anti-CD22 medicine, which work because the lymphoma kept the surface of the normal cell it came from"]},"route":"/pathways/germinal-centre-reaction/","neighbours":{"cancer":[{"id":"burkitt-lymphoma","kind":"cancer","name":"Burkitt lymphoma","route":"/cancers/burkitt-lymphoma/"},{"id":"dlbcl","kind":"cancer","name":"Diffuse large B-cell lymphoma","route":"/cancers/dlbcl/"},{"id":"follicular-lymphoma","kind":"cancer","name":"Follicular lymphoma","route":"/cancers/follicular-lymphoma/"},{"id":"non-hodgkin-lymphoma","kind":"cancer","name":"Non-Hodgkin lymphoma (all types)","route":"/cancers/non-hodgkin-lymphoma/"},{"id":"primary-mediastinal-b-cell-lymphoma","kind":"cancer","name":"Primary mediastinal (thymic) large B-cell lymphoma","route":"/cancers/primary-mediastinal-b-cell-lymphoma/"}],"target":[{"id":"bcl2","kind":"target","name":"BCL-2","route":"/targets/bcl2/"},{"id":"bcl6","kind":"target","name":"BCL6","route":"/targets/bcl6/"},{"id":"crebbp","kind":"target","name":"CREBBP","route":"/targets/crebbp/"},{"id":"ep300","kind":"target","name":"EP300","route":"/targets/ep300/"},{"id":"ezh2","kind":"target","name":"EZH2","route":"/targets/ezh2/"},{"id":"kmt2d","kind":"target","name":"KMT2D","route":"/targets/kmt2d/"},{"id":"myc-gene","kind":"target","name":"MYC","route":"/targets/myc-gene/"}],"pathway":[{"id":"bcr-signalling","kind":"pathway","name":"B-cell receptor / BTK signalling (to NF-κB)","route":"/pathways/bcr-signalling/"},{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/"},{"id":"apoptosis-bcl2","kind":"pathway","name":"Intrinsic apoptosis (BCL-2 family)","route":"/pathways/apoptosis-bcl2/"},{"id":"myc","kind":"pathway","name":"MYC","route":"/pathways/myc/"}],"term":[{"id":"cell-of-origin","kind":"term","name":"Cell of origin (GCB vs ABC)","route":"/terms/cell-of-origin/"},{"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":"lymphoma-bio-germinal-centre","kind":"term","name":"The germinal centre: why lymphoma starts where antibodies are made","route":"/terms/lymphoma-bio-germinal-centre/"}],"biomarker":[{"id":"bcl2-rearrangement","kind":"biomarker","name":"BCL2 rearrangement, t(14;18)","route":"/biomarkers/bcl2-rearrangement/"},{"id":"double-hit-rearrangement","kind":"biomarker","name":"Double-hit and triple-hit: MYC with BCL2 and BCL6 rearrangement","route":"/biomarkers/double-hit-rearrangement/"},{"id":"ezh2-y646-mutation","kind":"biomarker","name":"EZH2 gain-of-function mutation (Tyr646, originally Tyr641)","route":"/biomarkers/ezh2-y646-mutation/"}]}}