Myeloma-derived macrophage inhibitory factor regulates bone marrow stromal cell-derived IL-6 via c-MYC

Journal of Hematology & Oncology
Rachel E PiddockStuart A Rushworth

Abstract

Multiple myeloma (MM) remains an incurable malignancy despite the recent advancements in its treatment. The protective effects of the niche in which it develops has been well documented; however, little has been done to investigate the MM cell's ability to 're-program' cells within its environment to benefit disease progression. Here, we show that MM-derived macrophage migratory inhibitory factor (MIF) stimulates bone marrow stromal cells to produce the disease critical cytokines IL-6 and IL-8, prior to any cell-cell contact. Furthermore, we provide evidence that this IL-6/8 production is mediated by the transcription factor cMYC. Pharmacological inhibition of cMYC in vivo using JQ1 led to significantly decreased levels of serum IL-6-a highly positive prognostic marker in MM patients. Our presented findings show that MM-derived MIF causes BMSC secretion of IL-6 and IL-8 via BMSC cMYC. Furthermore, we show that the cMYC inhibitor JQ1 can reduce BMSC secreted IL-6 in vivo, irrespective of tumor burden. These data provide evidence for the clinical evaluation of both MIF and cMYC inhibitors in the treatment of MM.

Citations

Jan 16, 2019·International Journal of Molecular Sciences·Paolo GiannoniDaniela de Totero
Jul 3, 2019·Asia-Pacific Journal of Clinical Oncology·Xibao YuYixin Zeng
Nov 2, 2019·American Journal of Respiratory Cell and Molecular Biology·Ion CristóbalJesús García-Foncillas
Mar 13, 2020·Frontiers in Oncology·Charlotte HellmichStuart A Rushworth
Sep 18, 2020·International Journal of Molecular Sciences·Chia-Hung YenHui-Hua Hsiao
Feb 16, 2021·Pharmacology & Therapeutics·Dingyu HuJi Zhang
Sep 25, 2021·Advanced Healthcare Materials·Di WuYu Shrike Zhang

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Methods Mentioned

BETA
ELISA
flow cytometry
PCR

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HL
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