Whereas the expression of PYGO1 is impacted by the well-known TAK1 IKK2 cascade for SLAMF6 and IRF4 also the TAK1 p38 cascade seems to play a function. IgM mediated MYC inhibition is reversed by the PI3K inhibitor Ly294002. This demonstrates an involvement of PI3K signalling to inhibit aberrant MYC expression. In addition, an effect of JNK, IKK2 or PI3K inhibition on basal expression of MYC could be 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. Additionally, a tonic BCR signalling and PI kin ase activity in Burkitts lymphoma has been not too long ago described by Schmitz and co workers.
On the other hand, this link among tonic PI3K signalling and MYC expression has not been described in this publication. Interestingly, in this study therapy of BL lines with BKM120, a PI kinase inhibitor in clinical trials, or rapamycin, an inhibi tor with the mTORC1 complex, was toxic to most BL lines soon after four days. Hence, their rapamycin signature must be taken into account for future selelck kinase inhibitor investigations. Surpris ingly, IKK2 inhibition was connected using a significantly stron ger IgM mediated suppression of MYC expression. As a result, we observed a suppressive part of tonic IKK2 activity onto MYC expression in BL2 cells. This sheds new light onto the regulation of the ab errant expression of MYC.
Good and adverse signals from PI3K, MAPK and NF kB pathways can now be investigated in much more detail by way of example to be able to delin eate variations between BLs and DLBCLs characterized by a higher Myc index or MYC break. A comparable impact of PI3K inhibition as described for MYC is observed also for BCL6, LEF1 and BCL9. How ever, as for MYC, the expression inhibitor NLG919 of BCL6 or BCL9 is currently affected to some extend by Ly294002 in un stimulated BL2 cells. Thus, it’s tough to interpret these data for BCL6 and BCL9 to 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 key effects of kinase inhibition observed just after IgM treatment. As already noted above, in some instances the remedy of cells with inhibitors is connected with an enhanced activation or inhibition of respective genes.
For ex ample treatment of cells with Ly294002 led to a stron ger activation of EGR2 or CCR7 by IgM treatment. 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 after inhibition of particular kinases is shown, which includes effects of these inhibitors onto the basal expression levels of analysed genes as one example is MYC or BCL9.