Constitutive Activation of the Canonical NF-κB Signaling Pathway and Expanded Populations of Splenic Marginal Zone B Cells Characterize Em-BCL10 Transgenic Mice.

The BCL10 gene was isolated from the breakpoint region of the t(1;14)(p22;q32) chromosomal translocation, a recurrent chromosomal abnormality in mucosa-associated lymphoid tissue (MALT)-type lymphomas. The translocation results in constitutive over-expression and nuclear location of the BCL10 protein. To understand the physiological and pathogenic roles played by BCL10 in B-cell biology, a transgenic (TG) mouse model was developed with a human BCL10 gene driven by Em. The TG was expressed in thymic but not peripheral T cells and in the spleen; lymph nodes were negative. Although the lymphoid compartments of the TG mice were grossly normal, histologic studies showed the splenic marginal zone (MZ) to be significantly expanded and, in older mice, to compress the white pulp. In addition, about 10% of animals developed B-cell neoplasms by 18 months of age. By FACS analyses, the number of MZ B cells was increased nearly 2-fold, and both MZ and follicular (FOL) B cells exhibited a marked down-regulation of CD23 expression. In the peritoneum of TG mice, the B1a B-cell population was markedly reduced while the B1b subset was increased over 2-fold. Studies of purified MZ and FOL B cells from normal and TG mice showed that MZ B cells from TG mice had a survival advantage in culture. Studies of the canonical NF-κB signaling pathway that lies downstream from BCL10 showed that it was constitutively activated with high levels of nuclear p50 and p65 protein identified by Western blotting. Quantitative real-time RT-PCR analyses of purified splenic B cells from normal and TG mice for expression of 384 genes identified 44 with significant differences in expression. Almost half of these genes were known NF-κB targets and included genes known to influence B-cell survival (BAFF, IL-10) or associated with MZ lymphomas (S100A9). These results indicate that constitutive expression of BCL10 in B cells is not sufficient to induce transformation alone and that as-yet-unknown secondary mutations are required. Nonetheless, expression of BCL10 clearly resulted in constitutive activation of the canonical NF-κB signaling pathway and a prominent expansion of the MZ B-cell population, thereby setting the stage for later development of lymphomas.