MAGE-A inhibit apoptosis and promote proliferation in multiple myeloma through regulation of BIM and p21Cip1
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Anna Huo-Chang Mei1, Kaity Tung1, Jessie Han1, Deepak Perumal1, Alessandro Laganà2,3, Jonathan Keats4, Daniel Auclair5, Ajai Chari1, Sundar Jagannath1, Samir Parekh1 and Hearn Jay Cho1,5
1 Tisch Cancer Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
2 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
3 Institute for Next Generation Healthcare, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
4 Translational Genomics Research Institute, Phoenix, AZ, USA
5 The Multiple Myeloma Research Foundation, Norwalk, CT, USA
|Hearn Jay Cho,||email:||[email protected]|
Keywords: MAGE-A3; multiple myeloma; apoptosis; cell cycle regulation; DNA repair
Received: July 18, 2019 Accepted: January 29, 2020 Published: February 18, 2020
The type I Melanoma Antigen Gene (MAGE) A3 is a functional target associated with survival and proliferation in multiple myeloma (MM). To investigate the mechanisms of these oncogenic functions, we performed gene expression profiling (GEP) of p53 wild-type human myeloma cell lines (HMCL) after MAGE-A knockdown, which identified a set of 201 differentially expressed genes (DEG) associated with apoptosis, DNA repair, and cell cycle regulation. MAGE knockdown increased protein levels of pro-apoptotic BIM and of the endogenous cyclin-dependent kinase (CDK) inhibitor p21Cip1. Depletion of MAGE-A in HMCL increased sensitivity to the alkylating agent melphalan but not to proteasome inhibition. High MAGEA3 was associated with the MYC and Cell Cycling clusters defined by a network model of GEP data from the CoMMpass database of newly diagnosed, untreated MM patients. Comparative analysis of CoMMpass subjects based on high or low MAGEA3 expression revealed a set of 6748 DEG that also had significant functional associations with cell cycle and DNA replication pathways, similar to that observed in HMCL. High MAGEA3 expression correlated with shorter overall survival after melphalan chemotherapy and autologous stem cell transplantation (ASCT). These results demonstrate that MAGE-A3 regulates Bim and p21Cip1 transcription and protein expression, inhibits apoptosis, and promotes proliferation.
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