화학공학소재연구정보센터
Biochemical and Biophysical Research Communications, Vol.498, No.3, 502-508, 2018
Interferon gamma is a strong, STAT1-dependent direct inducer of BCL6 expression in multiple myeloma cells
B-cell CLL/lymphoma 6 (BCL6) is a transcriptional master regulator that can repress more than 1200 potential target genes. It exerts oncogenic effects through the inhibition of differentiation, DNA damage sensing and apoptosis in several human hematopoietic malignancies, including multiple myeloma (MM). The multifunctional cytokine interferon gamma (IFN gamma) exerts pro-apoptotic and anti-proliferative effects on MM cells in vitro, at least partially through the inhibition of the effects of interleukin 6 (IL6), one of the most important growth factor of MM and a strong inducer of BCL6 expression. However, IFN gamma was also reported to directly upregulate BCL6 in several cell types. These observations prompted us to analyze the effect of IFN gamma on BCL6 expression in MM cells. We discovered that among several myeloma growth/survival factors tested (including IL6, oncostatin M, insulin-like growth factor 1, tumor necrosis factor alpha and IFN alpha) IFN gamma was the strongest inducer of BCL6 mRNA and protein expression in MM cell lines. IFN gamma induced upregulation of BCL6 was dependent on the classical STAT1 signaling pathway, and affected both major BCL6 variants. Interestingly, although IFN alpha induced stronger STAT1 phosphorylation than IFN gamma, it only slightly upregulated BCL6 in MM lines. We proved that IFN alpha induced BCL6 upregulation was limited by the concomitant activation of STAT5 signaling. We assume that BCL6 upregulation may represent a potentially pro-tumorigenic effect of IFN gamma signaling in MM cells. (C) 2018 Elsevier Inc. All rights reserved.