Myeloma-derived macrophage inhibitory factor regulates bone marrow stromal cell-derived IL-6 via c-MYC
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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.
KeywordsMyeloma MIF cMYC BMSC Stromal IL-6 IL-8 Bone marrow
Bone marrow stromal cell
Macrophage migratory inhibitory factor
Despite significant recent advancements made in the treatment of multiple myeloma (MM), relapse remains inevitable and the disease presently remains incurable. This is attributable, in part, to the highly protective nature of the BM micro-environment niche in which the malignant plasma cells proliferate. Macrophage migratory inhibitory factor (MIF) is a cytokine associated with various roles  and is rapidly developing a pro-tumoral identity . Elevated MIF levels are described in MM and have been implicated in MM bone marrow homing and chemotherapy resistance ; however, the adaptive effect that MM-derived MIF has on the tumor microenvironment is not yet defined. Here, we investigate the function of MM-derived MIF in the MM microenvironment by examining its effects on bone marrow stromal cells (BMSC).
Despite MIF’s association with hematological malignancies, previous work has focused on the effects of MIF on the malignant cells rather than the supportive cells of the microenvironment . Here, we show that MM-derived MIF is pro-tumoral through induction of BMSC-derived IL-6/8. IL-6 is central to MM pathogenesis and primarily comes from the BMSC in the tumor micro-environment . Here, we place IL-6 downstream of MIF-induced BMSC activation [6, 7]. IL-8 expression in BMSC, which has been shown to parallel MM disease progression  and positively influence osteoclastogenesis in MM , was increased in BMSC in response to MIF. Furthermore, the BET-bromodomain inhibitor JQ1 significantly decreased IL-6/8 secretion in MIF-stimulated BMSC. In vivo use of JQ1 significantly reduced levels of murine IL-6 in the serum [5, 10, 11]. Taken together, this suggests that JQ1 is exerting anti-MM activity, in part, through a direct effect on BMSC via the inhibition of BMSC IL-6 (and IL-8) synthesis. This in turn could explain why BMSC do not appear to offer MM protection from JQ1 therapy.
The authors wish to thank The Norwich Research Park (NRP), BBSRC, The National Institutes for Health Research (UK), The Big C, and The Rosetrees Trust for funding. Additionally, we are grateful to Professor Richard Ball and Iain Sheriffs, Norwich tissue bank (UK) for help with sample collection. pCDH-luciferase-T2A-mCherry was kindly gifted from Prof. Dr. med. Irmela Jeremias, Helmholtz Zentrum München, Munchen, Germany.
REP receives funding from the Norwich Research Park doctoral training program partnership, which is supported by the BBSRC. CRM is funded by the Rosetrees Trust, MSS by The Big C, and MJA and KMB are supported by the Norwich and Norfolk University Hospital. SAR receives funding from the University of East Anglia.
Availability of data and materials
The datasets supporting the conclusions of this article are included within this article and additional files.
REP, AA, KMB and SAR designed the research; REP, MSS and SAR performed the research; REP and CRM carried out in vivo work; MJA and KMB provided essential knowledge and reagents; REP, KMB and SAR wrote the paper. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Informed consent was given in accordance with the Declaration of Helsinki and under approval from the Health Research Authority of the National Health Service, United Kingdom (07/H0310/146).
All animal experiments were performed in accordance with UK Home Office and University of East Anglia Animal Welfare Ethics Review Board regulations.
Consent for publication
Informed consent has been obtained from all patients (see above).
The authors declare that they have no competing interests.
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