Due to interleukin-6 type cytokine redundancy only glycoprotein 130 receptor blockade efficiently inhibits myeloma growth

Abstract

IntroductionMultiple myeloma (MM) is characterized by the expansion of clonal plasma cells within the bone marrow (BM), leading to an M-protein in serum, antibody deficiency, and skeletal destruction. Despite stem cell transplantation and novel therapies, the vast majority of patients with MM will eventually relapse and become refractory to standard therapy. Treatment strategies specifically targeting mechanisms of tumor growth and survival are being intensely explored in MM in order to improve © Ferrata Storti Foundation patient outcome. 1In the pathogenesis of MM, genetic changes drive the development of the malignant clone, but the interaction between the malignant plasma cells and the BM microenvironment has been shown to be equally important in mediating myeloma cell survival and progression.2 One of the established pathogenic key factors produced in the BM milieu is interleukin(IL)-6, which promotes the growth and survival of the malignant plasma cells and mediates drug resistance.3 While some myeloma cells produce their own IL-6, 4 bone marrow stromal cells (BMSCs) are the main source, establishing a strong paracrine growth stimulation. 5 Other sources of IL-6 in MM are macrophages, osteoblasts and osteoclasts; 2 eosinophils and megakaryocytes may also contribute. 6The receptor for IL-6 comprises a specific α-receptor, glycoprotein (gp) 80 (CD126), which, after ligand binding, recruits the gp130 receptor (IL6ST, CD130). Gp130 is the common signal transducer for a family of cytokines with pleiotropic and partly redundant activities.7 While signaling via IL-6 and IL-11 is initiated via gp130 homodimerization, the receptor complexes of other family members consist of heterodimers of gp130 with a second signaling molecule, most of which use the leukemia inhibitory factor receptor (LIFR). Leukemia inhibitory factor (LIF) and oncostatin M (OSM) directly induce gp130/LIFR heterodimerization without the involvement of other receptor components. Upon dimerization, associated Janus kinases (JAKs) become activated and phosphorylate specific tyrosine residues on the receptors, which serve as docking sites for transcription factors and adaptor proteins. The main signaling pathways induced by gp130 are the activation of STAT (signal transducer and activator of transcription)-3, the Ras-dependent mitogen-activated protein kinase (MAPK) cascade, and the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) pathway. 7,8The human plasma cell line INA-6 was generated in our laboratory from the pleural effusion of a patient with advanced plasma cell disease. 9 The survival of INA-6 cells in vitro is strictly dependent on exogenous IL-6 without growth response to other gp130 cytokines. With the establishment of a xenograft model in severe combined immune deficiency (SCID) mice using INA-6, a non-optimal environment devoid of human IL-6 was provided. Despite the fact that murine IL-6 is not active on human cells, plasma cell tumors developed over a period of up to five months. In serum and ascites of tumor-beari...

Cytokines Behavior in Multiple Myeloma Patients during Zoledronic Acid Treatment

“…In our result, as documented also by other investigators we observed a sharp and statistically significant increase in IL-6 and TNF-α median values on days 1 and 2 after zoledronic acid infusion [19,20].…”

Repurposing tofacitinib as an anti-myeloma therapeutic to reverse growth-promoting effects of the bone marrow microenvironment

“…While we were unable to identify these factors, we did rule out a number of cytokines highly secreted by HS5 cells. 30 Furthermore, given that murine IL-6 does not cross-react with the human IL-6 receptor, 41 our in vivo results also suggest that other factors in the murine marrow microenvironment can stimulate JAK-STAT signaling, which is then reversed by tofacitinib. Candidates include leukemia inhibitory factor (LIF), which cross-reacts between mouse and humans, 41 , 42 or the complex between murine IL-6 and soluble murine IL-6 receptor, both of which can stimulate JAK/STAT signaling in human cells.…”

3D genome of multiple myeloma reveals spatial genome disorganization associated with copy number variations

“…4b ). The pathway enrichment analysis showed that these genes are strongly associated with MM-related pathways, including the MAPK signaling pathway 38 , N-glycan biosynthesis 39 , TNF signaling pathway 40 and cytokine–cytokine receptor interaction pathway 41 (Fig. 5a ).…”