BET bromodomain inhibition by JQ1 suppresses interleukin-6 secretion in myeloma cells
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1
Brighton and Sussex Medical School, United Kingdom
Background: Multiple myeloma (MM) is a malignant and progressive tumour of plasma cells. Overproduction of interleukin-6 (IL-6), a pleiotropic cytokine, is believed to play an important role in the pathogenesis of MM. Consequently, research has focused on targeting IL-6 as a therapeutic strategy for MM. Bromodomains are a diverse family of protein interaction modules that have a vital role in transcriptional regulation. Recent studies using well-established models of inflammation have shown that inhibitors of the bromodomain and extraterminal (BET) family of proteins suppress the expression of several pro-inflammatory cytokines including IL-6. The aim of this study is to investigate the effect of JQ1, a small molecule bromodomain inhibitor, on human MM cells and IL-6 secretion.
Methods: Primary MM cells were isolated from venous blood of a patient with refractory MM. To explore the effect on IL-6 secretion, primary MM cells were pre-treated with various concentrations of JQ1 then stimulated with lipopolysaccharide (LPS) and an IL-6 ELISA was performed. The effect on cell viability was measured using the WST-1 assay.
Results: Pre-treatment of LPS stimulated primary MM cells with JQ1 led to a dose-dependent suppression of IL-6 secretion. In addition, JQ1 exposure caused a time-dependent decrease in primary MM cell viability.
Conclusion: Treatment with JQ1 is not only cytotoxic to primary MM cells but also suppresses secretion of IL-6. These findings suggest that bromodomain inhibitors such as JQ1 represent a promising new class of immunomodulatory compounds that are highly active against MM.
Acknowledgements
We would like to thank Professor Knapp (Structural Genome Consortium, University of Oxford) for kindly donating the bromodomain inhibitor, JQ1.
References
1. Lauta VM. Interleukin-6 and the network of several cytokines in multiple myeloma: an overview of clinical and experimental data. Cytokine (2001) 16: 79-86.
2. Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S, Chung CW, Chandwani R, Marazzi I, Wilson P, Coste H, White J, Kirilovsky J, Rice CM, Lora JM, Prinjha RK, Lee K, Tarakhovsky A. Suppression of inflammation by a synthetic histone mimic. Nature (2010) 468: 1119-23.
Keywords:
Interleukin-6,
BET Family,
Bromodomain inhibitor,
JQ1,
Multiple Myeloma
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Translational immunology and immune intervention
Citation:
Ghurye
RR,
Stewart
HJ and
Chevassut
TJ
(2013). BET bromodomain inhibition by JQ1 suppresses interleukin-6 secretion in myeloma cells.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00823
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Received:
19 Jun 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. Rohit R Ghurye, Brighton and Sussex Medical School, Brighton, BN1 9PS, United Kingdom, rohitghurye@doctors.org.uk