Nuclear factor κB activation and antiapoptosis in mucosa-associated lymphoid tissue lymphoma

Three distinct chromosomal translocations, t(11;18), t(1;14), and t(14;18), involving the API2-MALT1 fusion protein, BCL10, and MALT1 have been convincingly implicated in the pathogenesis of mucosa-associated lymphoid tissue (MALT) lymphomas. Recent genetic and biochemical studies have indicated that BCL10 and MALT1 form a physical and functional complex and are both essential for nuclear factor kappaB (NF-kappaB) activation by antigen. receptor stimulation in lymphocytes. API2-MALT1 can bypass the BCL10/MALT1 pathway linking to NF-kappaB activation, thereby inducing antigen receptor-independent events of lymphocytes. BCL10/MALT1- and API2-MALT1-induced NF-kappaB activation can be assumed to be able to contribute to antiapoptosis, probably through NF-kappaB-mediated up-regulation of several apoptotic inhibitor genes. We also have provided direct evidence that API2-MALT1 can exert an antiapoptotic effect, in part through its direct interaction with apoptotic regulators. We therefore hypothesize that the antiapoptotic effect of API2-MALT1 may be mediated by the interaction with apoptotic regulators as well as by the up-regulation of apoptotic inhibitor genes. Finally, we hope that further studies will stimulate research leading to the development of therapeutic drugs that specifically inhibit the antigen receptor-stimulated NF-kappaB activation pathway. Such drugs should be useful for interfering with inappropriate proliferation of lymphocytes associated with inflammatory and neoplastic disorders, including MALT lymphomas. (C) 2004 The Japanese Society of Hematology.