Publication Date:
2016-12-02
Description:
Type I Melanoma Antigen Genes of the MAGE-A family are commonly expressed in multiple myeloma (MM). Their frequency of expression is higher in patients who have relapsed after chemotherapy compared to newly diagnosed patients, with a significant association with progression of disease. MAGE were also associated with high-risk disease in gene expression profiling studies. They belong to the Cancer-Testis group of oncofetal genes that are normally restricted to germ cells and trophoblastic tissue, and are aberrantly expressed in a broad range of human cancers. Type I MAGE proteins partner with the RING domain protein Kap1 to form ubiquitin ligase complexes, and in laboratory models of solid tumors they ubiquitinylate cancer-associated targets involved in metabolism, autophagy, and metastasis. We demonstrated that expression of MAGE-A genes, especially MAGE-A3, was correlated with progression of disease in MM and that MAGE-A inhibit p53-dependent and independent apoptosis in MM cells. These results lead us to investigate the hypothesis that MAGE-A promote resistance to chemotherapy-induced apoptosis in MM cells. We performed gene expression profiling by RNAseq of primary tumor specimens from an open label phase 2 clinical trial of panobinostat, a pan-HDAC inhibitor approved for treatment of relapsed MM, in combination with lenalidomide and dexamethasone (NCT01651039). These GEP data were analyzed for differential expression based on progression free survival (PFS) 〈 90 days (short PFS) versus PFS 〉 90 days (long PFS). MAGE-A1 was the most overexpressed gene in the short PFS group compared to long (p
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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