Dll1/NOTCH interaction induces drug resistance to Bortezomib by two distinct mechanism in Multiple Myeloma

One of the greatest challenges in multiple myeloma (MM) treatment is to overcome drug resistance. Dll1 is a Notch ligand expressed in bone marrow (BM) stromal cells. We have demonstrated that the Notch pathway could be activated by coculture of MM cells with Dll1 overexpressing stromal (MS5.Dll1) cells. We found that Dll1/Notch interaction could induce drug resistance to the proteasome inhibitor bortezomib both in murine 5T33MM and in human RPMI8226 MM cells. In addition, the Notch pathway inhibitor, DAPT, could increase the sensitivity to bortezomib.
We observed that CD138- MM cells are less sensitive to bortezomib, have a higher Notch activation and a higher expression of ABCG2 and Cyp1a1, genes involved in drug resistance, compared to CD138+ MM cells. The Cyp1a1 activity in CD138- MM cells is much higher than that in CD138+ MM cells. After Dll1/Notch interaction, we detected an increased percentage of CD138- MM cells and a down-regulation of CD138 mRNA expression. This could be reverted by inhibiting the Notch pathway with DAPT. Similar results were found in human RPMI8226 cells. Furthermore, we found that the anti-apoptotic proteins Bcl-2, Mcl-1, Bcl-xl were up-regulated and the pro-apoptotic protein Bim was down-regulated after Dll1/Notch interaction in CD138+ MM cells, which also can contribute to Dll1/Notch induced drug resistance. In conclusion,
our data show that Dll1/Notch interaction can induce drug resistance to bortezomib, by shifting MM cells to a more resistant CD138- phenotype and by up-regulating anti-apoptotic proteins in CD138+ MM cells.