Epigenetic mechanisms of cell adhesion-mediated drug resistance in multiple myeloma

Furukawa, Yusuke; Kikuchi, Jiro

doi:10.1007/s12185-016-2048-5

Cited by 50 publications

(51 citation statements)

References 120 publications

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“…5 MM cells in contact with BMSCs and extracellular matrix components escape the effects of therapy through cell adhesion-mediated drug resistance. 6,7 MM-PCs achieve this by means of molecules of the integrin family, CD44, Syndecan-1 (CD138), Lymphocyte Function-Associated Antigen-1 (LFA-1), Mucin-1 antigen (MUC-1), Vascular Cell Adhesion Molecule-1 (VCAM-1) and Intercellular Adhesion Molecule-1 (ICAM-1). [8][9][10][11] In line with several observations, [12][13][14][15] Paiva et al 16 recently demonstrated that integrins and adhesion molecules are overexpressed in MM cells from patients with minimal residual disease compared with MM-PCs from newly diagnosed MM patients.…”

Section: Introductionmentioning

confidence: 99%

JAM-A as a Prognostic Factor and New Therapeutic Target in Multiple Myeloma

Solimando

Brandl

Martini

et al. 2016

Blood

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Cell adhesion in the multiple myeloma (MM) microenvironment is a mechanism by which MM plasma cells escape the effects of therapy and survive. To improve clinical strategies and overcome drug resistance, approaches directed to both MMPCs and bone marrow microenvironment are under investigation. Here, we examined the cell membrane protein Junctional adhesion molecule-A (JAM-A) as a clinical biomarker and novel therapeutic target for MM. We evaluated JAM-A expression by real time PCR (RT-PCR), flow cytometry and immunofluorescence microscopy in 132 MM patients at different stages and various MM cell lines. Next, we measured the concentrations of soluble JAM-A from MM and healthy subjects sera by enzyme linked immune assay (ELISA). We investigated JAM-A functionally in vitro and in vivo by transient gene silencing (siRNA) and with blocking antibodies. Patient-derived plasma cells (MMPCs) expressed increased JAM-A expression levels when compared to control PC from healthy individuals. Elevated JAM-A expression correlated with poor prognosis (Figure 1A,B). Furthermore, soluble JAM-A was significantly increased in MM patient sera when compared to healthy subjects. Additionally, MM cell lines showed high expression of both membrane and cytoplasmic JAM-A. Consequently, inhibition of JAM-A using specific siRNA treatment resulted in diminished tumorigenic potential, including decreased colony formation, chemotaxis and migration. Importantly, treatment of luciferase+RPMI-8226 MM bearing NSG with a JAM-A blocking monoclonal antibody reduced significantly MM progression and dissemination in vivo when compared to MM bearing mice that received an non-specific isotype control antibody (Figure 1C). Conclusively, our data suggest that JAM-A can serve as a biomarker of malignancy in MM patients. Soluble plasma JAM-A could contribute to serum-based clinical stratification. Furthermore, therapeutic targeting of JAM-A appears attractive for clinical translation. Figure 1 Figure 1. Disclosures Einsele: Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria.

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Section: Introductionmentioning

confidence: 99%

JAM-A as a Prognostic Factor and New Therapeutic Target in Multiple Myeloma

Solimando

Brandl

Martini

et al. 2016

Blood

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“…S7B for data quantification). In addition, we examined the status of EZH2 and its specific target site H3K27, because cell adhesion diminishes the abundance of H3K27me3 via EZH2 inactivation, leading to the transactivation of prosurvival genes in MM cells (5,6). As anticipated, the methylation level of H3K27 was remarkably diminished in parallel with phosphorylation and downregulation of EZH2 in MM cells under adherent and hypoxic conditions ( Fig.…”

Section: Regulation Of Cd180 Promoter By Ikzf1 Transcription Factor (mentioning

confidence: 69%

“…It is widely accepted that relapse stems from dormant and highly drug-resistant clones in the MM compartment. Drugresistant clones are kept dormant via interaction with bone marrow stroma cells (BMSC) in a hypoxic microenvironment (3)(4)(5)(6). Elucidation of the mechanisms underlying the regrowth of dormant clones may prolong remission and ultimately improve the survival of MM patients.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we have identified a novel epigenetic mechanism of drug resistance in which BMSCs reduce the abundance of trimethylated histone H3 at lysine-27 (H3K27me3), a hallmark of condensed chromatin at silent loci, via EZH2 inactivation to derepress the transcription of several antiapoptotic genes in MM cells (5,6). The derepressed gene products include CD180, a homolog of Toll-like receptor 4 (TLR4), originally identified as 105 kDa protein (RP105) that imparts the resistance to radiation and corticosteroids in Blymphocytes (7,8).…”

Section: Introductionmentioning

confidence: 99%

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Myeloma Cells Are Activated in Bone Marrow Microenvironment by the CD180/MD-1 Complex, Which Senses Lipopolysaccharide

et al. 2018

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Multiple myeloma (MM) cells acquire dormancy and drug resistance via interaction with bone marrow stroma cells (BMSC) in a hypoxic microenvironment. Elucidating the mechanisms underlying the regrowth of dormant clones may contribute to further improvement of the prognosis of MM patients. In this study, we find that the CD180/MD-1 complex, a noncanonical lipopolysaccharide (LPS) receptor, is expressed on MM cells but not on normal counterparts, and its abundance is markedly upregulated under adherent and hypoxic conditions. Bacterial LPS and anti-CD180 antibody, but not other Toll-like receptor ligands, enhanced the growth of MM cells via activation of MAP kinases ERK and JNK in positive correlation with expression levels of CD180. Administration of LPS significantly increased the number of CD180/CD138 double-positive cells in a murine xenograft model when MM cells were inoculated with direct attachment to BMSC. Knockdown of CD180 canceled the LPS response and Promoter analyses identified IKZF1 (Ikaros) as a pivotal transcriptional activator of the gene. Both cell adhesion and hypoxia activated transcription of the gene by increasing Ikaros expression and its binding to the promoter region. Pharmacological targeting of Ikaros by the immunomodulatory drug lenalidomide ameliorated the response of MM cells to LPS in a CD180-dependent manner and Thus, the CD180/MD-1 pathway may represent a novel mechanism of growth regulation of MM cells in a BM milieu and may be a therapeutic target of preventing the regrowth of dormant MM cells. This study describes a novel mechanism by which myeloma cells are regulated in the bone marrow, where drug resistance and dormancy can evolve after treatment, with potential therapeutic implications for treating this often untreatable blood cancer. .

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“…Histone methylation is, like DNA methylation, one of the most studied epigenetic modifications on histones. It can be linked to active transcription (e.g., H3K4me1/me2/m3, HK36me3, H3K79me1/me2/me3, H4R3me1, H4K20me1) or to gene silencing (e.g., H3K9me2/me3, H3K27me3) [10,11]. Histone methyltransferases (HMT) use, as DNMTs, the SAM cofactor to mono-, di- or tri-methylate lysine residues (thus known as HKMT, histone lysine methyltransferases) or to mono- or di-methylate arginine residues (thus known as PRMT, protein arginine N -methyltransferases) of the core or tails of histones [12].…”

Section: Introductionmentioning

confidence: 99%

DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge

et al. 2017

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Chromatin can adopt a decondensed state linked to gene transcription (euchromatin) and a condensed state linked to transcriptional repression (heterochromatin). These states are controlled by epigenetic modulators that are active on either the DNA or the histones and are tightly associated to each other. Methylation of both DNA and histones is involved in either the activation or silencing of genes and their crosstalk. Since DNA/histone methylation patterns are altered in cancers, molecules that target these modifications are interesting therapeutic tools. We present herein a vast panel of DNA methyltransferase inhibitors classified according to their mechanism, as well as selected histone methyltransferase inhibitors sharing a common mode of action.

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Epigenetic mechanisms of cell adhesion-mediated drug resistance in multiple myeloma

Cited by 50 publications

References 120 publications

JAM-A as a Prognostic Factor and New Therapeutic Target in Multiple Myeloma

JAM-A as a Prognostic Factor and New Therapeutic Target in Multiple Myeloma

Myeloma Cells Are Activated in Bone Marrow Microenvironment by the CD180/MD-1 Complex, Which Senses Lipopolysaccharide

DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge

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