Molecular pathogenesis of MALT lymphoma: two signaling pathways underlying the antiapoptotic effect of API2-MALT1 fusion protein

Abstract

At least three recurrent chromosomal translocations, t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), involving the API2-MALT1 fusion protein, BCL10 and MALT1, have been implicated in the pathogenesis of mucosa-associated lymphoid tissue (MALT) lymphoma. Several lines of evidence indicated that both BCL10 and MALT1 are required for nuclear factor kappa B (NF-jB) activation by antigen receptor stimulation in lymphocytes, and API2-MALT1 can bypass this BCL10/MALT1 signaling pathway. Nuclear factor kappa B activation may contribute to antiapoptotic effect through NF-jB-mediated upregulation of apoptotic inhibitor genes. We recently demonstrated that API2-MALT1 can induce transactivation of the API2 gene through NF-jB activation, thus highlighting a positive feedback-loop mechanism of self-activation by upregulating its own expression in t(11;18) MALT lymphomas. We also demonstrated that API2-MALT1 possesses an antiapoptotic effect, in part, through its direct interaction with apoptotic regulators. These findings therefore led us to hypothesize that the antiapoptotic effect by API2-MALT1 may be mediated by its interaction with apoptotic regulators, on the one hand, and by NF-jB-mediated upregulation of apoptotic inhibitor genes on the other. We also found that BCL10 and MALT1 are shuttling between nucleus and cytoplasm, and that MALT1 can regulate the subcellular location of BCL10. Leukemia (2006) 20, 929-936.

Establishment of a novel MALT lymphoma cell line, ma‐1, from a patient with t(14;18)(q32;q21)‐positive Helicobacter Pylori‐Independent Gastric MALT Lymphoma

“…Apart from the t(11;18)(q21;q21) and t(1;14)(p22;q32) translocations, t(14;18)/IGH-MALT1, involving the MALT1 and IGH genes and resulting in the overexpression of MALT1, is the best-known and well-described translocation in MALT lymphomas (Sanchez-Izquierdo et al, 2003;Streubel et al, 2003). The translocation may deregulate MALT1, which would subsequently recruit and stabilize BCL10 and CARMA1 and trigger aberrant NFKB activation, thereby contributing to the proliferation of MALT lymphoma (Sanchez-Izquierdo et al, 2003;Streubel et al, 2003;Nakagawa et al, 2006). It occurs in some non-gastric MALT lymphoma originating from liver, lung, ocular adnexa, salivary gland, and skin (Streubel et al, 2004;Remstein et al, 2006;Palmedo et al, 2007) but only occasionally in gastric MALT lymphoma (Streubel et al, 2004;Remstein et al, 2006;Nakamura et al, 2007a).…”

TNFAIP3 is the target gene of chromosome band 6q23.3‐q24.1 loss in ocular adnexal marginal zone B cell lymphoma

“…Certain chromosomal translocations, t(11;18) (q21;q21), t(1;14)(p22;q32), and t(14;18)(q32;q21), have been implicated in the pathogenesis of MZBCL, and it has been shown that these genetic aberrations utilize a common signaling pathway by ultimately targeting the same nuclear factor kappa B (NF-kB) signaling pathway (Lucas et al, 2001;Nakagawa et al, 2006). Ye et al (2003) reported that RT-PCR analysis identified the t(11;18)(q21;q21) in 16.3% of ocular adnexal MZBCL.…”

Mucosa-Associated Lymphoid Tissue Lymphoma: Novel Translocations Including Rearrangements of ODZ2, JMJD2C, and CNN3

“…The molecular genetics underlying the pathogenesis of MALT lymphoma are only recently being understood in detail for the three MALT-specific translocations t(11;18)/API2-MALT1, t(1;14)/IGH-BCL10, and t(14;18)/IGH-MALT1 (19). Antigen stimulation and CD40 triggering synergize in NF-nB activation through the formation of a CARMA1-BCL10-MALT1 ternary complex.…”

“…DNA of patients 1,4,18,19,20,22,26, and 28 was isolated from the fresh tumor samples using a High Pure PCR Template Preparation kit (Roche). The long-distance inverse PCR (LDI-PCR) for the joining and switch regions was done as described previously (9,10).…”