Involvement of the Tis11b/Berg36 Family in the Regulation of B-CLL Surivival and Differentiation.

Tis11b/Berg36 is a member of a family of proteins involved in post-transcriptional gene regulation. Members of this family bind to AU rich elements in certain mRNA species and increase mRNA stability. mRNA that contain AU rich elements and can be regulated in this way include molecules involved in the regulation of apoptosis eg bcl-2 and several cytokines eg TNF, IL-2. We have recently shown that Tis11b/Berg36 is involved in the regulation of apoptosis following Rituximab treatment of CLL cells suggesting a pro-apoptotic role of this gene in CLL cells. Thus B-CLL were stimulated with IL-4, anti-CD40, anti-CD40+IL-4 and PMA. It was found that IL-4, CD40 and their combination significantly inhibited spontaneous apoptosis while PMA was able to inhibit spontaneous apoptosis in some but not all patients tested and the overall effect did not reached statistical significance. Unexpectedly Tis11b/Berg36 mRNA remained unchanged following IL-4 treatment, but expression was induced following anti-CD40 or PMA treatment. Because it was found that regulation of Tis11b/Berg36 mRNA following the latter two treatments was under the control of NF-κB pathway and not p38 (as found for Rituximab treatment) it was hypothesized that this gene may be involved in the regulation of cell cycle or differentiation of B-CLL cells. Indeed it was found that stimulation of B-CLL cells with either PMA or anti-CD40 resulted in increase in sIgM as a marker of B-CLL differentiation. CLL cells were also found to express high basal levels of two other members of this family, Tis11 and Tis11d. From these stimuli, IL-4 or anti-CD40 were found to downregulate the basal expression of Tis11 mRNA. These data suggest that members of the Tis11b/Berg36 family are involved in the regulation of apoptosis and differentiation in B-CLL cells.