{"entity":{"id":"lymphoma-bio-germinal-centre","kind":"term","name":"The germinal centre: why lymphoma starts where antibodies are made","aka":["Germinal centre reaction","Somatic hypermutation","Class switch recombination","Affinity maturation"],"tldr":"To make a better antibody, a B cell has to deliberately damage its own DNA while dividing fast, with its safety checks switched off. Most B-cell lymphomas are cells that went into that process and never came out of it properly.","summary":"A germinal centre forms in a lymph node a few days after a new infection or vaccination. Inside it, a B cell switches on an enzyme called activation-induced cytidine deaminase, which mutates the part of its own DNA that codes for the binding end of the antibody. Cells whose antibody now binds better are kept, the rest die, and the process repeats. The same enzyme cuts and rejoins the gene to change antibody class. This is why a second dose of a vaccine works better than the first.\n\nIt is also the most dangerous thing a healthy cell does. To survive deliberate DNA damage while dividing rapidly, the cell switches off its damage response, through the transcriptional repressor BCL6, and locks the exit shut, through the polycomb complex and its enzyme EZH2. A cell in that state is a cancer waiting for one mistake.\n\nThe mistakes are specific and recognisable. The t(14;18) translocation that puts BCL2 under an antibody gene's control is a recombination error, and the sequence of the breakpoints shows it was made by the normal recombinase at the pre-B-cell stage rather than later (Tsujimoto 1985). MYC lands next to an immunoglobulin locus the same way in Burkitt lymphoma. EZH2 gain-of-function mutations keep the exit locked. CREBBP and EP300 loss, present in about 39% of diffuse large B-cell lymphoma and 41% of follicular lymphoma, leaves BCL6 switched on when it should be off (Pasqualucci 2011).\n\nTwo practical consequences follow. First, a lymphoma usually keeps the surface of the normal B cell it came from, which is why CD19, CD20, CD79b and CD22 antibodies work. Second, a t(14;18)-carrying B cell can be found in the blood of healthy people, so the first lesion is not the disease; what makes a lymphoma is what happens afterwards.","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":"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":"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"}],"tags":[],"related":[],"cancers":["non-hodgkin-lymphoma","dlbcl","follicular-lymphoma","burkitt-lymphoma"],"sections":[],"technologies":[],"targets":["bcl6","ezh2","crebbp","ep300","bcl2","myc-gene"],"drugs":[],"companies":[],"institutions":[],"pathways":["germinal-centre-reaction","epigenetic-reprogramming"],"terms":["cell-of-origin","cytogenetics","gene-fusion","driver-mutation"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"category":"Cancer biology"},"route":"/terms/lymphoma-bio-germinal-centre/","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":"malt-lymphoma","kind":"cancer","name":"Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)","route":"/cancers/malt-lymphoma/"},{"id":"follicular-lymphoma","kind":"cancer","name":"Follicular lymphoma","route":"/cancers/follicular-lymphoma/"},{"id":"mantle-cell-lymphoma","kind":"cancer","name":"Mantle cell lymphoma","route":"/cancers/mantle-cell-lymphoma/"},{"id":"non-hodgkin-lymphoma","kind":"cancer","name":"Non-Hodgkin lymphoma (all types)","route":"/cancers/non-hodgkin-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":"myc-gene","kind":"target","name":"MYC","route":"/targets/myc-gene/"}],"pathway":[{"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":"germinal-centre-reaction","kind":"pathway","name":"The germinal centre reaction","route":"/pathways/germinal-centre-reaction/"}],"term":[{"id":"cell-of-origin","kind":"term","name":"Cell of origin (GCB vs ABC)","route":"/terms/cell-of-origin/"},{"id":"cytogenetics","kind":"term","name":"Cytogenetics and karyotype","route":"/terms/cytogenetics/"},{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"},{"id":"flipi","kind":"term","name":"FLIPI, FLIPI2 and POD24 (follicular lymphoma risk)","route":"/terms/flipi/"},{"id":"gene-fusion","kind":"term","name":"Gene fusion","route":"/terms/gene-fusion/"}],"technology":[{"id":"clonality-testing","kind":"technology","name":"Immunoglobulin and T-cell receptor clonality testing","route":"/technologies/clonality-testing/"}],"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/"},{"id":"ig-tcr-clonality","kind":"biomarker","name":"Immunoglobulin and T-cell receptor clonality","route":"/biomarkers/ig-tcr-clonality/"}]}}