Purpose Multiple myeloma (MM) is a life-threatening disease and despite the introduction of stem cell transplantation and novel agents such as thalidomide, lenalidomide, and bortezomib most patients will relapse and develop chemoresistant disease. Therefore, alternative therapeutic modes for myeloma are needed and cancer-testis (CT) antigens such as MAGE-C1/CT7 and MAGE-A3 have been suggested to represent a class of tumor-specific proteins particularly suited for targeted immunotherapies. Surprisingly, the biological role of CT genes in myeloma remains poorly understood. Experimental Design We performed the first investigation of the function of two CT antigens most commonly expressed in myeloma, MAGE-C1/CT7 and MAGE-A3, using an RNAi based gene silencing model in myeloma cell lines. Functional assays were used to determine changes in proliferation, cell adhesion, chemosensitivity, colony formation, and apoptosis resulting from gene-specific silencing. RESULTS: We show that the investigated genes are not involved in regulating cell proliferation or adhesion, however, they play an important role in promoting the survival of myeloma cells. Accordingly, knockdown of MAGE-C1/CT7 and MAGE-A3 led to the induction of apoptosis in the malignant plasma cells and, importantly, both genes were also essential for the survival for clonogenic myeloma precursors. Finally, silencing of CT genes further improved the response of myeloma cells to conventional therapies. Conclusions CT antigens such as MAGE-C1/CT7 and MAGE-A3 play an important role in promoting survival of myeloma cells and clonogenic precursors by reducing the rate of spontaneous and chemotherapy-induced apoptosis and might therefore represent attractive targets for novel myeloma-specific therapies.
Purpose Multiple myeloma (MM) is a life-threatening disease and despite the introduction of stem cell transplantation and novel agents such as thalidomide, lenalidomide, and bortezomib most patients will relapse and develop chemoresistant disease. Therefore, alternative therapeutic modes for myeloma are needed and cancer-testis (CT) antigens such as MAGE-C1/CT7 and MAGE-A3 have been suggested to represent a class of tumor-specific proteins particularly suited for targeted immunotherapies. Surprisingly, the biological role of CT genes in myeloma remains poorly understood. Experimental Design We performed the first investigation of the function of two CT antigens most commonly expressed in myeloma, MAGE-C1/CT7 and MAGE-A3, using an RNAi based gene silencing model in myeloma cell lines. Functional assays were used to determine changes in proliferation, cell adhesion, chemosensitivity, colony formation, and apoptosis resulting from gene-specific silencing. RESULTS: We show that the investigated genes are not involved in regulating cell proliferation or adhesion, however, they play an important role in promoting the survival of myeloma cells. Accordingly, knockdown of MAGE-C1/CT7 and MAGE-A3 led to the induction of apoptosis in the malignant plasma cells and, importantly, both genes were also essential for the survival for clonogenic myeloma precursors. Finally, silencing of CT genes further improved the response of myeloma cells to conventional therapies. Conclusions CT antigens such as MAGE-C1/CT7 and MAGE-A3 play an important role in promoting survival of myeloma cells and clonogenic precursors by reducing the rate of spontaneous and chemotherapy-induced apoptosis and might therefore represent attractive targets for novel myeloma-specific therapies.