H pylori and gastric MALT lymphomagenesis paradigm for infection-associated indirect lymphoid transformation. (A) Persisting antigens (Ag's) elicit a polyclonal B-cell response. Costimulation is provided by cytokines and members of the tumor necrosis factor superfamily (CD40-CD40L in T-cell–dependent responses and B-cell activating factor [BAFF]/B-lymphocyte stimulator [BLyS] or a proliferation-inducing ligand [APRIL] produced by dendritic cells in T-cell–independent responses). In the case of H pylori, T cells specific for H pylori epitopes provide help to B cells that recognize cross-reactive autoantigens present in the gastric mucosa such as fucosylated sialyl–Lewis X through CD40-CD40L costimulation. (B) Occurrence of genetic events such as p15 and p16 hypermethylation provide a selective advantage leading to the outgrowth of an antigen-responsive clone. Antigen dependence reflects the requirement for BCR signals such as NF-κB activation (see also Figure 5). (C) Progression toward antigen-independent (therefore antimicrobial-insensitive) MALT lymphoma is associated with the occurrence of additional genetic events. Chromosomal translocations involving MALT1 and Bcl-10 lead to a constitutive activation of NF-κB, bypassing the requirement for BCR-dependent signals (Figure 5). The t(11;18) translocation occurs early during B-cell proliferation and accelerates the transformation process in an antigen-independent fashion. The t(1;14) and t(14;18) translocations also lead to BCR-dependent NF-κB activation, but occur later after an antigen-dependent phase and can be associated with additional cytogenetic abnormalities. The t(3;14) translocation produces an IgH-FoxP1 transcript in 10% of MALT lymphomas that do not harbor other translocations involving the MALT1/Bcl-10 pathway. The precise role of t(3;14) is not known. P53 mutation is associated with transformation to high-grade lymphoma.