The germinal centre reaction

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.

Almost 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.

The 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.