scholarly journals Potential crosstalk of the interleukin-6-heme oxygenase-1-dependent mechanism involved in resistance to lenalidomide in multiple myeloma cells

FEBS Journal ◽  
2016 ◽  
Vol 283 (5) ◽  
pp. 834-849 ◽  
Author(s):  
Weibing Wu ◽  
Dan Ma ◽  
Ping Wang ◽  
Lu Cao ◽  
Tangsheng Lu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Heme Oxygenase ◽  
Interleukin 6 ◽  
Heme Oxygenase 1 ◽  
Myeloma Cells ◽  
Dependent Mechanism

scholarly journals Potential Crosstalk of Interleukin-6-Heme Oxygenase-1 Dependent Mechanism Involved in Resistance to Lenalidomide in Multiple Myeloma Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4856-4856
Author(s):  
Jishi Wang ◽  
Weibing Wu ◽  
Dan Ma ◽  
Ping Wang ◽  
Lu Cao ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Mrna Expression ◽  
Heme Oxygenase ◽  
Interleukin 6 ◽  
Conflicts Of Interest ◽  
Janus Kinase ◽  
Heme Oxygenase 1 ◽  
Expression Levels

Abstract Interleukin-6 (IL-6), as one of the most important multiple myeloma (MM) survival factors, has been verified to determine poor prognosis of MM. IL-6 mainly originates from paracrine of bone marrow stromal cells and autocrine of MM cells. As an enzyme having cytoprotective effects, heme oxygenase-1 (HO-1) promotes the growth and drug resistance of various malignant tumors. The HO-1 expression levels in bone marrow CD138+ cells of MM patients, which were significantly higher than those of healthy donors, were positively correlated with serum IL-6 levels and intracellular IL-6 mRNA expression levels. Cultivating U266 and CD138+ cells with exogenous IL-6 in vitro induced high HO-1 expressions and allowed them to resist lenalidomide, probably because IL-6 activated the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway. Without IL-6 co-culture, on the other hand, up-regulating HO-1 expressions in U266 cells and bone marrow CD138+ cells from MM patients significantly up-regulated the mRNA expression level of IL-6 and facilitated autocrine IL-6 production. The findings were associated with high HO-1 expression-enhanced of p38 MAPK phosphorylation. Down-regulating HO-1 expression sensitized U266 and CD138+ cells toward lenalidomide. Therefore, we postulated that HO-1 predominantly controlled IL-6 paracrine and autocrine, and that IL-6 in bone marrow microenvironment of MM patients stimulated MM cells to highly express HO-1 and to resist lenalidomide. High HO-1 expression also stimulated autocrine IL-6 production, thus further augmenting the drug resistance and exacerbating the disease. This study provides valuable experimental evidence for using HO-1 as a possible marker for MM prognosis and drug resistance and as a potential treatment target. Disclosures No relevant conflicts of interest to declare.

Bortezomib Could Reduce Cell Viability by Activation of Heme Oxygenase 1 in Multiple Myeloma Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5005-5005 ◽  
Author(s):  
Daniele Tibullo ◽  
Cesarina Giallongo ◽  
Ignazio Barbagallo ◽  
Piera La Cava ◽  
Nunziatina Parrinello ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Viability ◽  
Heme Oxygenase ◽  
Colorimetric Assay ◽  
Heme Oxygenase 1 ◽  
Off Label Use ◽  
Myeloma Cells ◽  
Bortezomib Treatment ◽  
Thrombopoietin Receptor ◽  
Thrombopoietin Receptor Agonist

Abstract Abstract 5005 Bortezomib (PS-341, Velcade®) specifically targeting the ubiquitin-proteosome pathway, is the first defined therapeutic proteosoma inhibitor approved by FDA for treatment of Multiple Myeloma (MM). We explored the hypothesis that the activity of Bortezomib in MM cells may involve the heme oxygenase 1 (HMOX1), a enzyme with pleiotropic effects, catalysing the degradation of heme to carbon monoxide, biliverdin and ferrous iron. After 24h of treatment with Bortezomib at 10nM, the U266 and SKM-M1 MM cell lines showed a decrease of cell viability around 50% and an increase of HMOX1 protein and mRNA expression of 40 fold (p<0. 001). Using a colorimetric assay we observed that Bortezomib increased also the HMOX1enzymatic activity (p<0. 03). To elucidate the significance of the HMOX1 increase after bortezomib treatment, we treated myeloma cells with Bortezomib plus an inducer (Hemin 10uM) or an inhibitor (Tin, Sn-Mesoprotoporphyrin, 10uM) of the enzyme activity. Treatment with Hemin and Tin alone not changed the cell viability. Cell viability was reduced (p<0. 003) by addition of Hemin and was increased (p<0. 002) by Tin addiction with respect to Bortezomib alone. Conclusion: Bortezomib increases HMOX1expression and its enzymatic activity and this increase could be an important mechanism of Bortezomib induced cytotoxicity in MM cells. Modulation of HMOX1 activity has effect on Bortezomib induced cell death. Disclosures: Off Label Use: Eltrombopag is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP).

scholarly journals B cells suppress medullary granulopoiesis by an extracellular glycosylation-dependent mechanism

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Eric E Irons ◽  
Melissa M Lee-Sundlov ◽  
Yuqi Zhu ◽  
Sriram Neelamegham ◽  
Karin M Hoffmeister ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Cells ◽  
Progenitor Cell ◽  
Hematopoietic Progenitors ◽  
Myeloma Cells ◽  
Human B Cells ◽  
Extrinsic Cues ◽  
Bone Marrow Niches ◽  
Dependent Mechanism

The immune response relies on the integration of cell-intrinsic processes with cell-extrinsic cues. During infection, B cells vacate the marrow during emergency granulopoiesis but return upon restoration of homeostasis. Here we report a novel glycosylation-mediated crosstalk between marrow B cells and hematopoietic progenitors. Human B cells secrete active ST6GAL1 sialyltransferase that remodels progenitor cell surface glycans to suppress granulopoiesis. In mouse models, ST6GAL1 from B cells alters the sialylation profile of bone marrow populations, and mature IgD+ B cells were enriched in sialylated bone marrow niches. In clinical multiple myeloma, ST6GAL1 abundance in the multiple myeloma cells negatively correlated with neutrophil abundance. These observations highlight not only the ability of medullary B cells to influence blood cell production, but also the disruption to normal granulopoiesis by excessive ST6GAL1 in malignancy.

Blockade of SDF‐1/CXCR4 reduces adhesion‐mediated chemoresistance of multiple myeloma cells via interacting with interleukin‐6

2019 ◽  
Vol 234 (11) ◽  
pp. 19702-19714 ◽  
Author(s):  
Ying Liu ◽  
Hai‐Mei Liang ◽  
Yu‐Qi Lv ◽  
Shao‐Mei Tang ◽  
Peng Cheng
Keyword(s):  
Multiple Myeloma ◽  
Interleukin 6 ◽  
Myeloma Cells

scholarly journals Interleukin-6 is a potent myeloma-cell growth factor in patients with aggressive multiple myeloma

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 11-13 ◽  
Author(s):  
XG Zhang ◽  
B Klein ◽  
R Bataille
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Cell Growth ◽  
Interleukin 6 ◽  
Myeloma Cell ◽  
S Phase ◽  
Myeloma Cells ◽  
Severity Of The Disease

Abstract It has recently been demonstrated that interleukin-6 (IL-6) is a potent myeloma-cell growth factor in the majority of patients with multiple myeloma (MM). Using an anti-bromodeoxyuridine monoclonal antibody (MoAb) to specifically count myeloma cells in the S-phase (ie, labeling index, LI), we demonstrate that the IL-6 responsiveness of myeloma cells in vitro is directly correlated with their LI in vivo. Myeloma cells from all 13 patients with high LIs in vivo (greater than or equal to 1%) responded in vitro to IL-6, the strongest response occurring in cells from five patients with plasma-cell leukemia. In contrast, the cells of only two of eight patients with low myeloma-cell LIs in vivo (less than 1%) responded to IL-6 in vitro. After seven days of culturing with 1,000 U/mL recombinant IL-6 (rIL-6), the median LI value in the first group of patients (in vivo LI greater than or equal to 1%) was 11%, ie 11 times higher (P less than .01) than the median LI value (1%) in the second group of patients (in vivo LI less than 1%). Thus, the in vitro IL-6 responsiveness of myeloma cells is directly related to their in vivo proliferative status, and hence to the severity of the disease.

A gp130 Interleukin-6 Transducer-Dependent SCID Model of Human Multiple Myeloma

Blood ◽  
1998 ◽  
Vol 91 (12) ◽  
pp. 4727-4737 ◽  
Author(s):  
Cosette Rebouissou ◽  
John Wijdenes ◽  
Patrick Autissier ◽  
Karin Tarte ◽  
Valerie Costes ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Interleukin 6 ◽  
Myeloma Cell ◽  
Scid Mice ◽  
Term Survival ◽  
Myeloma Cells ◽  
Tumoral Cells ◽  
Human Myeloma Cells

Agonist antihuman gp130 transducer monoclonal antibodies (MoAbs) were used in SCID mice to grow myeloma cells whose survival and proliferation is dependent on gp130 transducer activation. The agonist anti-gp130 MoAbs neither bound to murine gp130 nor activated murine cells and, as a consequence, did not induce interleukin-6 (IL-6)–related toxicities in mice. They have a 2-week half-life in vivo when injected in the peritoneum. The agonist antibodies made possible the in vivo growth of exogenous IL-6–dependent human myeloma cells as well as that of freshly explanted myeloma cells from 1 patient with secondary plasma cell leukemia. Tumors occurred 4 to 10 weeks after myeloma cell graft and weighed 3 to 5 g. They grew as solid tumors in the peritoneal cavity and metastasized to the different peritoneal organs: liver, pancreas, spleen, and intestine. Tumoral cells were detected in blood and bone marrow of mice grafted with the XG-2 myeloma cells. Tumoral cells grown in SCID mice had kept the phenotypic characteristics of the original tumoral cells and their in vitro growth required the presence of IL-6 or agonist anti-gp130 MoAbs. Myeloma cells from 4 patients with medullary involvement persisted for more than 1 year as judged by detectable circulating human Ig. However, no tumors were detected, suggesting a long-term survival of human myeloma cells without major proliferation. These observations paralleled those made in in vitro cultures as well as the tumor growth pattern in these patients. This gp130 transducer-dependent SCID model of multiple myeloma should be useful to study various therapeutical approaches in multiple myeloma in vivo.

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