Cancer-testis antigens MAGE-C1/CT7 and MAGE-A3 promote the survival of multiple myeloma cells

Abstract

BackgroundMultiple myeloma 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 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 cancer-testis genes in myeloma remains poorly understood. Design and MethodsWe performed the first investigation of the function of two cancer-testis antigens most commonly expressed in myeloma, MAGE-C1/CT7 and MAGE-A3, using an RNA interferencebased 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. ResultsWe 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, knock-down 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 of clonogenic myeloma precursors. Finally, silencing of cancer-testis genes further improved the response of myeloma cells to conventional therapies. ConclusionsCancer-testis antigens such as MAGE-C1/CT7 and MAGE-A3 play an important role in promoting the 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.Key words: cancer-testis antigens, gene function, RNAi, apoptosis, tumor immunology, multiple myeloma, stem cell transplantation.Citation: Atanackovic D, Hildebrandt Y, Jadczak A, Cao Y, Luetkens T, Meyer S, Kobold S, Bartels K, Pabst C, Lajmi N, Gordic M, Stahl T, Zander AR, Bokemeyer C, promote the survival of multiple myeloma cells. Haematologica 2010;95:785-793. doi:10.3324/haematol.2009 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n Cancer-testis antigens MAGE-C1/CT7 and MAGE-A3 promote the survival of multiple myeloma cells

Cancer testis antigens in newly diagnosed and relapse multiple myeloma: prognostic markers and potential targets for immunotherapy

“…46 A functional role for CTAs in MM ties in with the finding of CTA expression post relapse in this study. Finally, CTA expression has been reported in cancer stem cells, among others in melanoma and glioma.…”

MageA2 restrains cellular senescence by targeting the function of PMLIV/p53 axis at the PML-NBs

“…Nevertheless, in the last years compelling evidence has accumulated suggesting that individual MAGE proteins could behave in specific pathways critical for tumor progression. [30][31][32][33][34] We previously demonstrated that MageA2 is a relevant player in favoring chemoresistance to p53 bearing human melanoma cells. Here, we analyze the role of MageA2 as regulator of another important tumor-suppressive mechanism, namely cellular senescence.…”

Cancer/Testis Antigen Expression Panel Incorporating MAGEC1 and BAGE2 Predicts Multiple Myeloma Disease Stage and Severity

“…We propose that the following pattern of expression occurs during disease: MAGEC1 -PRAME -MAGEA3 -PAGE-BAGE2 -NYESO1/SSX2. The idea of a cascade-like expression of CTAs has been previously suggested [17,38], with their role being linked with promoting the survival of MM cells by decreasing transcription factors that control cell proliferation or induce apoptosis and regulation of cell signalling and gene transcription [17,19,20,43,44].…”

“…MAGEA3 occurred in 79% of SMM patients and was again associated with advanced disease [17,19] with 21/23 patients in this cohort diagnosed with stage III MM. There was a very strong correlation between expression of this CTA and anemia (p ˂0.0005), with an average Hb value of 9.0 for this group.…”

“…Although the full panel of CTAs has yet to be tested in MM patients, the following CTAs have been found to be expressed in 20-80% of cases: MAGEC1 and MAGE A3/6, SP-17, PRAME, NYESO1, SSX family (1,2,5) and BAGE [15][16][17][18][19]. While commonly expressed, the role in MM pathogenesis is unclear, with hints at a possible cascade-like effect occurring where the expression of multiple CTAs appears to be associated with advanced disease [17,19,20].…”