Inhibition of caspase-8 activity caused by overexpression of BCL10 contributes to the pathogenesis of high-grade MALT lymphoma.

BACKGROUND

Mucosa-associated lymphoid tissue (MALT) lymphoma comprises approximately 8% of all non-Hodgkin lymphomas and is the most common lymphoma in the gastro-intestinal tract. It is caused by genetic abnormalities or bacterial infections/chronic inflammation. B-cell lymphoma/leukemia 10 (BCL10) overexpression and nuclear expression have been associated with high-grade MALT lymphomas with genetic abnormalities that are unresponsive to Helicobacter pylori eradication treatment. To explore the molecular mechanism of BCL10 overexpression on the pathogenesis and malignant phenotype of MALT lymphoma, we generated EµSR-BCL10 transgenic mice.

PROCEDURE: By generation of heterozygous and homozygous EuSR-BCL10 mice and showing BCL10 expression levels in these mice, we quantitatively examined relation of MZ B cell expansion and inhibition of caspase-8 activity with BCL10 protein level. We also investigated API2 and caspase-8 expression by Western blot and their interaction with BCL10 by co-immunoprecipitation.

RESULTS

MZ B-cell expansion is directly related to BCL10 protein level in a dose-dependent manner. The activity of caspases-8 and -3, but not caspase-9, was inhibited with increasing of BCL10 protein level. Expanded MZ B cells showed selective survival under stimulation of anti-immunoglobulin M, but not dexamethasone, γ-irradiation, or anti-CD95, implying that overexpressed BCL10 exerts anti-apoptotic effects through B-cell antigen receptor (BCR) pathway. Overexpressed BCL10 protein co-immunoprecipitated with caspase-8 and API2 protein, suggesting an in vivo interaction of them.

CONCLUSION

Our data demonstrate a novel effect of overexpressed BCL10 in the pathogenesis of high-grade MALT lymphoma by increasing expression of API2 and it then forming a protein complex with BCL10/caspase-8 leading to caspase-8 activity suppression.