Whereas the expression of PYGO1 is impacted by the well-known TAK1 IKK2 cascade for SLAMF6 and IRF4 also the TAK1 p38 cascade appears to play a role. IgM mediated MYC inhibition is reversed by the PI3K inhibitor Ly294002. This demonstrates an involvement of PI3K signalling to inhibit aberrant MYC expression. Moreover, an effect of JNK, IKK2 or PI3K inhibition on basal expression of MYC is usually observed. This supports a function of a tonic activation of PI3K, JNK and IKK2 mediated signalling activity in regulating aberrant basal MYC expression. Interestingly, a brand new murine model for lymphomas has been described supporting the view of a synergistic action of c Myc and PI3K signalling. Furthermore, a tonic BCR signalling and PI kin ase activity in Burkitts lymphoma has been lately described by Schmitz and co workers.
On the other hand, this hyperlink involving tonic PI3K signalling and MYC expression has not been described within this publication. Interestingly, within this study treatment of BL lines with BKM120, a PI kinase inhibitor in clinical trials, or rapamycin, an inhibi tor from the mTORC1 complicated, was toxic to most BL lines just after 4 days. Thus, their rapamycin signature has to be taken into account for future mTOR kinase assay investigations. Surpris ingly, IKK2 inhibition was linked with a considerably stron ger IgM mediated suppression of MYC expression. Therefore, we observed a suppressive function of tonic IKK2 activity onto MYC expression in BL2 cells. This sheds new light onto the regulation with the ab errant expression of MYC.
Optimistic and negative signals from PI3K, MAPK and NF kB pathways can now be investigated in additional detail for example so as to delin eate differences between BLs and DLBCLs characterized by a high Myc index or MYC break. A comparable effect of PI3K inhibition as described for MYC is observed also for BCL6, LEF1 and BCL9. How ever, as for MYC, the expression additional resources of BCL6 or BCL9 is currently impacted to some extend by Ly294002 in un stimulated BL2 cells. Therefore, it is difficult to interpret these information for BCL6 and BCL9 towards the end. We speculate that combinations of pathways are involved in both basal and IgM mediated gene expression. In Figure 7A a scheme summarizes the principle effects of kinase inhibition observed just after IgM therapy. As already noted above, in some instances the remedy of cells with inhibitors is linked with an enhanced activation or inhibition of respective genes.
For ex ample remedy of cells with Ly294002 led to a stron ger activation of EGR2 or CCR7 by IgM remedy. Comparable effects are observed for IKK2 inhibition for SLAMF3 and ID3, for p38 or JNK inhibition analysing SGK1, ID3 or PYGO1 respectively. In Figure 7B a respective sum mary of most important IgM enhancing effects soon after inhibition of distinct kinases is shown, like effects of these inhibitors onto the basal expression levels of analysed genes as by way of example MYC or BCL9.