While T and B cell antigen receptor (TCR/BCR) signaling induces the recruitment of BCL10 bound to mucosa-associated lymphoid tissue (MALT)1 to the lymphocyte-specific CARMA1/CARD11-BCL10-MALT1 (CBM-1) signalosome, alternative CBM complexes utilize different CARMA/CARD scaffolds in distinct innate or inflammatory pathways.
We previously reported that activation of the B-cell-activating factor (BAFF) pathway upregulates nuclear factor-κB (NF-κB) and induces BCL3 and BCL10 nuclear translocation in Helicobacter pylori (HP)-independent gastric diffuse large B-cell lymphoma (DLBCL) tumours with evidence of mucosa-associated lymphoid tissue (MALT).
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.
Our series revealed t(14;18) (q32;q21) in 6/43 cases (14,3%). t(1;14) (p22;q32), never described in ocular adnexa MALT lymphomas, was observed in 3/31 (9,7%), two of which exhibited the gain of 3' upstream BCL10 gene signal (4%), whereas no case showed t(11;18) (q21;q21).
We investigated the expression of Bcl10 gene mutations in mucosa-associated lymphoid tissue-type ocular adnexal lymphoma (OAL), atypical lymphoid hyperplasia (ALH), and reactive lymphoid hyperplasia (RLH) in the Chinese population and its role in clinical diagnosis and pathogenesis.
Few cases of breast MALT lymphomas in the literature have been assessed for MALT lymphoma-associated translocations and BCL10 expression, underlying their rarity in primary breast MALT lymphomas.
Mucosa-associated lymphoid tissue (MALT) lymphoma is characterized by t(11;18)(q21;q21)/API2-MALT1, t(1;14)(p22;q32)/BCL10-IGH and t(14;18)(q32;q21)/IGH-MALT1, which commonly activate the nuclear factor (NF)-kappaB pathway.
As we observed MALT1-API2 to be an efficient target of its own E3 ubiquitin ligase activity, our data suggest that this inherent instability of MALT1-API2 prevents its accumulation and renders a potential effect on MALT lymphoma development via destabilization of BCL10 unlikely.
BCL10, required for nuclear factor kappaB (NF-kappaB) activation during antigen-driven lymphocyte responses, is aberrantly expressed in mucosa-associated lymphoid tissue-type marginal zone (MZ) lymphomas because of chromosomal translocations.
We investigated the efficacy of H. pylori eradication and assessed the predictive value of BCL10 nuclear expression and t(11;18)(q21;q21) regarding resistance to H. pylori eradication in primary gastric mucosa-associated lymphoid tissue lymphoma (MALT lymphoma) patients from mainland China.
Translocations involving IGH were detected in 36 (32%) of 111 cases; their partner genes included BCL6 (n = 10), c-MYC (n = 5), and FOXP1 (n = 3) but remained unknown in the remaining 18 cases. t(14;18)/IGH-BCL2, t(14;18)/IGH-MALT1, and t(1;14)/BCL10-IGH were not detected in any case. t(11;18)/API2-MALT1 was detected in none of the cases, except for one case of DLBCL with MALT lymphoma, which showed positive signals only in MALT lymphoma cells.
We assessed the incidence and clinical significance of the MALT lymphoma-associated genetic abnormalities t(11;18)/API2-MALT1, t(1;14)/BCL10-IGH, t(14;18)/IGH-MALT1, t(3;14)/FOXP1-IGH, and extra copies of MALT1 and FOXP1 in gastric MALT lymphomas from Japan.
Our results showed five key findings, which are (a) higher detection rates of t(11;18) (21.13%) in Chinese patients with transformed MALT lymphoma, (b) lower detection rates of t(11;18) in stomach MALT lymphoma, (c) different organ localizations of MALT lymphoma in Chinese patients, (d) higher nuclear expression rates of Bcl-10 in low grade MALT (51.72%), and (e) lower response rates (50% CR, and 50% PR) to anti-H.-pylori therapy.
Further, all four patients with differential response of MALToma and DLBCL to HPET showed nuclear expression of BCL10 in the H. pylori-independent component and cytoplasmic expression of BCL10 in the H. pylori-dependent component while the expression patterns of BCL10 were identical in both of these components in the 14 patients who had similar tumour response to HPET.
Bcl10 is a caspase-recruitment domain-containing protein, associated with constitutive activation of NF-kappaB in MALT (mucosa-associated lymphoid tissue) lymphomas.
We have recently shown that nuclear translocation of Bcl10 is a specific molecular determinant of Helicobacter pylori-independent mucosa-associated lymphoid tissue lymphoma (Kuo, S.-H., Chen, L. T., Yeh, K.-H., Wu, M. S., Hsu, H. C., Yeh, P. Y., Mao, T. L., Chen, C. L., Doong, S. L., Lin, J. T., and Cheng, A.-L. (2004) J. Clin.Oncol.22, 3491-3497).
Apoptosis regulator B-cell lymphoma 10 (BCL10) may show aberrant nuclear localization in some aggressive extracutaneous MALT lymphomas, often in association with a MALT1 gene t(11;18)(q21;q21) translocation.
Here we show that cIAP2 is a ubiquitin ligase (E3) of BCL10 and targets it for degradation, inhibiting antigen receptor-mediated cytokine production. cIAP2-MALT1 lacks E3 activity, and concomitantly, the BCL10 protein is stabilized in MALT lymphomas harboring this fusion.
This study further supports the close interaction between the MALT1 and BCL10 proteins in the pathogenesis of MALT lymphomas and may indicate that BCL10 immunohistochemistry is a simple technique to identify those MALT lymphoma cases with an underlying genetic aberration.