Abstract
BackgroundMultiple myeloma (MM), characterized by cancerous proliferation of plasmablasts (PB) and plasma cells (PC), remains incurable in many patients. Differentially expressed molecules between MM PCs and healthy PCs have been explored in order to identify novel targets for treating MM. In the present study, we searched for novel MM therapeutic targets by comparing mRNA expression patterns between the Mus musculus myeloma plasmablast-like SP 2/0 cell line and LPS-induced PB/PC.MethodsGene expression profiles of LPS-induced PB/PC and SP 2/0 cells were determined using RNA-sequencing. A predicted gene (Gm40600) was found to be expressed at a low level in SP 2/0 cells. To study the role of Gm40600 in malignant PC, Gm40600 cDNA was cloned into a lentiviral vector (LV201) containing a puromycin selectable marker that was then transfected into SP 2/0 cells. Stable Gm40600-expressing SP 2/0 cells were selected using puromycin. The effect of Gm40600 on SP 2/0 cell proliferation, cell cycle/apoptosis, and tumor progression was assessed by cell counting kit-8 (CCK8), flow cytometry (FACS), and the SP 2/0 isograft mouse model, respectively. The effect of Gm40600 on mRNA and protein expression was evaluated by RNA-sequencing and western blotting, respectively.ResultsWe found that SP 2/0 cells expressed lower level of Gm40600 mRNA as compared to LPS-induced PB/PC. Overexpression of Gm40600 significantly suppressed SP 2/0 cell proliferation and isograft tumor progression in an isograft mouse model by promoting apoptosis. In addition, Gm40600 overexpression suppressed transcription of the gene encoding Bcl2. Gm40600 overexpression also reduced the expression of PC-associated transcription factors Blimp1 and Xbp1, which promote transcription of the gene that encodes Bcl2.ConclusionsGm40600 reduced SP 2/0 cell proliferation and isograft tumor growth and progression by suppressing Blimp1 and Xbp1-mediated Bcl2 transcription to induce apoptosis. Thus, regulation of a human homolog of Gm40600, or associated factors, may be a potential therapeutic approach for treating MM.
Highlights
Multiple myeloma (MM), characterized by cancerous proliferation of plasmablasts (PB) and plasma cells (PC), remains incurable in many patients
SP 2/0 cells express low levels of Gm40600 mRNA Plasmablasts (PB) induced by LPS [20, 22] and the Mus musculus myeloma PB-like SP 2/0 cells were used as normal PB/plasma cells (PC) and MM PB/PC, respectively
Both LPS-stimulated PB/PC and SP 2/0 cells expressed high levels of mRNA corresponding to the following PB/PC-associated transcription factors IRF4, Prdm1 (Blimp1), and Xbp1 (Table 1)
Summary
Multiple myeloma (MM), characterized by cancerous proliferation of plasmablasts (PB) and plasma cells (PC), remains incurable in many patients. Expressed molecules between MM PCs and healthy PCs have been explored in order to identify novel targets for treating MM. We searched for novel MM therapeutic targets by comparing mRNA expression patterns between the Mus musculus myeloma plasmablastlike SP 2/0 cell line and LPS-induced PB/PC. Deaths due to multiple myeloma (MM) with malignant plasma cells (PC) [1] is approximately 1% of all cancer deaths [2, 3]. This is mainly because of the following two reasons: (1) MM is still incurable in many patients [4, 5]; (2) some patients are refractory to current. Because we found that Mus musculus myeloma PB-like SP 2/0 cells (MM PB/PC) expressed a significantly lower level of Gm40600 (a predicted gene) mRNA as compared to LPS-induced PB/PC (normal PB/PC), the effect of Gm40600 on SP 2/0 cell growth was tested
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