Anti-Notch treatment prevents multiple myeloma cells localization to the bone marrow via the chemokine system CXCR4/SDF-1

Mirandola L, Apicella L, Chiriva-Internati M and Chiaramonte R. Leukemia. (2013) 27, 1558–1566

Speaker: Yi-Ying Tsai (蔡怡瑩)                                    Time: 13:10~14:00, Oct. 02, 2013

Commentator: Dr. Hsiao-Sheng Liu (劉校生 博士)    Place: Room 601

Abstract

   Multiple myeloma (MM) is a cancer of plasma cells. It results from clonal proliferation and accumulation of malignant plasma cells in the bone marrow (BM). Within the symptoms, more than 80% of patients develope osteolytic bone disease (1). Though the treatment of MM is advanced to date, it’s still incurable. The interaction between MM cells and bone marrow stromal cells plays an important role in disease progression and chemotherapeutic resistance (2). Previous studies showed that CXCR4 and its ligand Stromal Cell-Derived Factor-1 (SDF-1) induced tumor cellsmigration to the BM and the level of SDF-1 positively related with osteolysis. These results emphasize the correlation of CXCR4/SDF-1 axis and MM (3). Deregulation of Notch signaling pathway in MM cells affects multiple symptoms of MM, including tumor cells growth and drug resistance. In addition, Notch signaling regulates the function of chemokine receptors, including CXCR4 (4). Therefore, the authors hypothesized that CXCR4/SDF-1 axis may participate in the Notch signaling pathway in MM. Accordingly, they found that inhibition of Notch signaling by γ-secretase inhibitor XII (GSI-XII) affected MM cells growth and apoptosis rate. Downregulation of CXCR4 and SDF-1 expression of cells by GSI-XII treatment, suggesting that Notch activation in MM cells positively controlled the expression and function of CXCR4 and SDF-1. Moreover, activation of CXCR4 by exogenous SDF-1 rescued MM cells from the negative effect of Notch inhibition. Inhibition of Notch signaling pathway reduced CXCR4 expression and infiltration of MM cells to the bone marrow in NOD/SCID xenografts. Taken together, these results provide a new therapeutic way to prevent MM cells accumulating in the bone marrow via targeting Notch signaling.

References

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2.      Harousseau JL. et al. Autologous hematopoietic stem-cell transplantation for multiple myeloma. N Engl J Med. 360:2645-54. (2009).

3.      Zannettino AC. et al. Elevated serum levels of stromal-derived factor-1 alpha are associated with increased osteoclast activity and osteolytic bone disease in multiple myeloma Patients. Cancer Res. 65(5):1700-9. (2005).

4.      Colombo M. et al. Notch-directed microenvironment reprogramming in myeloma: a single path to multiple outcomes. Leukemia. 27(5):1009-18. (2013)