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Induction of Apoptosis in Plasma Cells by B Lymphocyte–Induced Maturation Protein-1 Knockdown

¹ Genomics Research Center, Academia Sinica; ² Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan

Requests for reprints: Kuo-I Lin, Genomics Research Center, Academia Sinica, 128 Academia Road, Section 2, Nankang District, Taipei 115, Taiwan. Phone: 886-2-2789-9930, ext. 336; Fax: 886-2-2789-9931; E-mail: kuoilin{at}gate.sinica.edu.tw.

B lymphocyte–induced maturation protein-1 (Blimp-1) is a transcriptional repressor that plays an important role during plasmacytic differentiation and is expressed in normal and transformed plasma cells. We here investigated the importance of continuous Blimp-1 expression. We found that knockdown of Blimp-1 expression by lentiviral vector-delivered short hairpin RNA causes apoptosis in multiple myeloma cell lines and plasmacytoma cells, indicating that continued expression of Blimp-1 is required for cell survival. We examined the mechanism underlying Blimp-1 knockdown-mediated apoptosis and found that the Blimp-1 knockdown neither reversed the phenotypic markers of plasma cells nor caused cell cycle arrest. Instead, our results show that knockdown of Blimp-1 induced the proapoptotic protein Bim, reduced the antiapoptotic protein Mcl-1, and activated caspase-9 and caspase-3. We further link apoptosis in transformed plasma cells mediated by proteasome inhibitors, the effective therapeutic agent for multiple myeloma patients, with reduced expression of Blimp-1. Lastly, we show that Blimp-1–dependent cell survival may act downstream of IFN regulatory factor 4 (IRF4) because IRF4 knockdown leads to down-regulation of Blimp-1 and apoptosis in multiple myeloma cells and plasmacytoma cells. Together, our data suggest that Blimp-1 ensures the survival of transformed plasma cells. [Cancer Res 2007;67(24):11914–23]

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