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An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells
Published on: July 15, 2015
Interferon γ is a strong, STAT1-dependent direct inducer of BCL6 expression in multiple myeloma cells
Dorina Ujvari1, Noemi Nagy2, Harsha S Madapura2
1Department of Women`s and Children`s Health, Karolinska Institutet, Stockholm, Sweden.
Abstract:
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 γ (IFNγ) 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, IFNγ was also reported to directly upregulate BCL6 in several cell types. These observations prompted us to analyze the effect of IFNγ 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 α and IFNα) IFNγ was the strongest inducer of BCL6 mRNA and protein expression in MM cell lines. IFNγ induced upregulation of BCL6 was dependent on the classical STAT1 signaling pathway, and affected both major BCL6 variants. Interestingly, although IFNα induced stronger STAT1 phosphorylation than IFNγ, it only slightly upregulated BCL6 in MM lines. We proved that IFNα 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 IFNγ signaling in MM cells.
Insights
Interferon gamma (IFNγ) strongly increases BCL6 expression in multiple myeloma (MM) cells, potentially promoting tumor growth. This IFNγ-induced BCL6 upregulation is mediated by STAT1 signaling.
Area of Science:
- Hematology
- Molecular Biology
- Cancer Research
Background:
- B-cell CLL/lymphoma 6 (BCL6) is a key transcriptional regulator implicated in hematopoietic malignancies like multiple myeloma (MM).
- Interferon gamma (IFNγ) typically exhibits anti-cancer effects in MM by inhibiting growth factors like interleukin 6 (IL6), but can also upregulate BCL6.
- The dual role of IFNγ necessitates understanding its precise effects on BCL6 in MM.
Purpose of the Study:
- To investigate the effect of IFNγ on BCL6 expression in multiple myeloma (MM) cells.
- To elucidate the signaling pathways involved in IFNγ-mediated BCL6 regulation in MM.
Main Methods:
- Treatment of MM cell lines with various growth factors, including IFNγ and IFNα.
- Analysis of BCL6 mRNA and protein expression levels.
- Investigation of STAT1 and STAT5 signaling pathway activation using phosphorylation assays.
Main Results:
- IFNγ was identified as the strongest inducer of BCL6 mRNA and protein expression among tested factors in MM cell lines.
- IFNγ-induced BCL6 upregulation was dependent on the STAT1 signaling pathway and affected both major BCL6 variants.
- IFNα induced STAT1 phosphorylation but only slightly upregulated BCL6, with STAT5 activation limiting this effect.
Conclusions:
- IFNγ significantly upregulates BCL6 expression in multiple myeloma cells via STAT1 signaling.
- This BCL6 upregulation by IFNγ may represent a pro-tumorigenic mechanism in MM.
- Differential STAT activation by interferons (IFNγ vs. IFNα) influences BCL6 expression differently in MM.
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