MALT lymphoma: A paradigm of NF-κB dysregulation

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) invariably arises from a background of chronic microbial infection and/or autoimmune disorder at diverse mucosal sites. The prolonged chronic infection and/or autoimmunity generate active immune and inflammatory responses that provide a setting for evolution and development of autoreactive B-cells, their expansion and eventual malignant transformation following acquisition of genetic changes. The immune responses also play a critical role in sustaining the growth and survival of the transformed cells as shown by complete regression of a high proportion of MALT lymphoma of the stomach, ocular adnexa and skin following anti-microbial treatment. B-cell receptor engagement by auto-antigen as well as T-cell help including both cognate interaction and bystander help via soluble ligands such as CD40L and BAFF are thought to underpin the immunological drive in the lymphoma development through activation of the canonical and non-canonical NF-κB pathway respectively. Similarly, the three MALT lymphoma associated chromosome translocations, namely t(1;14)(p22;q32)/BCL10-IGH, t(14;18)(q32;q21)/IGH-MALT1,and t(11;18)(q21;q21)/BIRC3 (API2)-MALT1, are also capable of activating both canonical and non-canonical NF-κB pathways. Furthermore, TNFAIP3 (A20) inactivation by deletion and/or mutation abolishes the auto-negative feedback to several signalling including BCR and TLR, which connect to the canonical NF-κB activation pathway. Thus, there is a considerable overlap in the molecular pathways dysregulated by immunological drive and somatic genetic changes, strongly arguing for their oncogenic cooperation in the development of MALT lymphoma.