Notch signaling and multiple myeloma: challenging endogenous and bone marrow-mediated drug resistance

BACKGROUND: Multiple myeloma (MM) is an hematologic tumor caused by the accumulation of malignant plasma cells in the bone marrow (BM). The dysregulated expression of two Notch ligands, Jagged1 and Jagged2, hyperactivates the Notch pathway both in MM cells and in BM stromal cell (BMSC) (1). Several Notch downstream mediators are involved in MM cell survival and proliferation, i.e. IL6, SDF1α, CXCR4, NF-kB, VEGF and IGF. MM remains incurable, principally due to the development of endogenous or BM-mediated drug resistance (DR). Therefore it is crucial to find new therapeutic targets. EXPERIMENTAL MODEL: MM cells were cultured alone or on a BMSC monolayer, Jag1 and Jag2 expression was knocked down using two specific shRNA and cells were treated with Mitoxantrone, Bortezomib, Melphalan or vehicle control. Apoptosis was determined by Annexin V-FITC staining; different expression of anti-apoptotic factors was evaluated by flow-citometry and by qRT-PCR. RESULTS: Results showed an increased sensitivity to drugs used and a decreased expression of SDF1α, CXCR4, Bcl-XL, Bcl-2, Survivin and ABCC1. In co-colture with BMSCs, MM cells showed increased DR due to: the increased expression of anti-apoptotic genes in MM cells; the released by BMSC of soluble mediators crucial for MM cells survival. We suggest that these effects may be driven by the reciprocal activation of Notch signaling observed in both cell types and consistently we demonstrated that DR may be significantly reduced by silencing Jagged1 and 2 in MM cells. CONCLUSION: The evidence that Jagged1/2 silencing affects endogenous and BMSC-induced DR in MM cells supports the use of a Jagged-tailored approach in MM therapy. REFERENCES: 1. Houde C, et al. Overexpression of the NOTCH ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines. Blood. 2004;104(12):3697-704