Cereblon Enhancer Methylation and IMiD Resistance in Multiple Myeloma

Blood ◽  
2021 ◽  
Author(s):  
Larissa Haertle ◽  
Santiago Barrio ◽  
Umair Munawar ◽  
Seungbin Han ◽  
Xiang Zhou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
In Vitro Experiments ◽  
Immunomodulatory Drugs ◽  
Dna Hypermethylation ◽  
Direct Binding ◽  
Underlying Mechanisms ◽  
Over Time

Cereblon is the direct binding target of the immunomodulatory drugs that are commonly used to treat Multiple Myeloma, the second most frequent hematologic malignancy. Patients respond well to initial IMiD treatment but virtually all develop drug resistance over time with the underlying mechanisms poorly understood. We identified a yet undescribed DNA hypermethylation in an active intronic CRBN enhancer. Differential hypermethylation in this region was found increased in healthy plasma cells, but more pronounced in IMiD refractory MM. Methylation significantly correlated with decreased CRBN expression levels. DNTMi in vitro experiments induced CRBN enhancer demethylation and sensitizing effects on Lenalidomide treatment were observed in two MM cell lines. Thus, we provide first evidence that aberrant CRBN DNA methylation is a novel mechanism of IMiD resistance in Multiple Myeloma and may predict IMiD response prior treatment.

scholarly journals Identification of the Cysteine Protease Legumain as a Potential Chronic Hypoxia-Specific Multiple Myeloma Target Gene

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 292
Author(s):  
Ada-Sophia Clees ◽  
Verena Stolp ◽  
Björn Häupl ◽  
Dominik C. Fuhrmann ◽  
Frank Wempe ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cysteine Protease ◽  
Chronic Hypoxia ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Low Oxygen ◽  
Clonal Proliferation ◽  
Temporal Adaptation ◽  
Specific Regulation

Multiple myeloma (MM) is the second most common hematologic malignancy, which is characterized by clonal proliferation of neoplastic plasma cells in the bone marrow. This microenvironment is characterized by low oxygen levels (1–6% O2), known as hypoxia. For MM cells, hypoxia is a physiologic feature that has been described to promote an aggressive phenotype and to confer drug resistance. However, studies on hypoxia are scarce and show little conformity. Here, we analyzed the mRNA expression of previously determined hypoxia markers to define the temporal adaptation of MM cells to chronic hypoxia. Subsequent analyses of the global proteome in MM cells and the stromal cell line HS-5 revealed hypoxia-dependent regulation of proteins, which directly or indirectly upregulate glycolysis. In addition, chronic hypoxia led to MM-specific regulation of nine distinct proteins. One of these proteins is the cysteine protease legumain (LGMN), the depletion of which led to a significant growth disadvantage of MM cell lines that is enhanced under hypoxia. Thus, herein, we report a methodologic strategy to examine MM cells under physiologic hypoxic conditions in vitro and to decipher and study previously masked hypoxia-specific therapeutic targets such as the cysteine protease LGMN.

scholarly journals tRNA Derivatives in Multiple Myeloma: Investigation of the Potential Value of a tRNA-Derived Molecular Signature

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1811
Author(s):  
Paraskevi Karousi ◽  
Aristea-Maria Papanota ◽  
Pinelopi I. Artemaki ◽  
Christine-Ivy Liacos ◽  
Dimitrios Patseas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
In Silico Analysis ◽  
Staging System ◽  
Molecular Signature ◽  
Real Time Quantitative Pcr ◽  
Favorable Prognosis ◽  
Clonal Proliferation

Multiple myeloma (MM) is a hematologic malignancy arising from the clonal proliferation of malignant plasma cells. tRNA-derived RNA fragments (tRFs) constitute a class of small non-coding RNAs, deriving from specific enzymatic cleavage of tRNAs. To the best of our knowledge, this is one of few studies to uncover the potential clinical significance of tRFs in MM. Total RNA was extracted from CD138+ plasma cells of MM and smoldering MM patients, and in vitro polyadenylated. First-strand cDNA synthesis was performed, priming from an oligo-dT-adaptor sequence. Next, real-time quantitative PCR (qPCR) assays were developed for the quantification of six tRFs. Biostatistical analysis was performed to assess the results and in silico analysis was conducted to predict the function of one of the tRFs. Our results showed that elevated levels of five out of six tRFs are indicators of favorable prognosis in MM, predicting prolonged overall survival (OS), while two of them constitute potential molecular biomarkers of favorable prognosis in terms of disease progression. Moreover, three tRFs could be used as surrogate prognostic biomarkers along with the R-ISS staging system to predict OS. In conclusion, tRFs show molecular biomarker utility in MM, while their mechanisms of function merit further investigation.

scholarly journals Whole-Genome Epigenomic Analysis in Multiple Myeloma Reveals DNA Hypermethylation of B-Cell Specific Enhancers

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2032-2032
Author(s):  
Xabier Agirre ◽  
Giancarlo Castellano ◽  
Marien Pascual ◽  
Simon Health ◽  
Marta Kulis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Epigenetic Modification ◽  
Cpg Islands ◽  
Whole Genome ◽  
B Cell Differentiation ◽  
Dna Hypermethylation

Abstract Analyzing the DNA methylome of multiple myeloma (MM), a plasma cell neoplasm, by whole-genome bisulfite sequencing and high-density arrays, we observed regional DNA hypermethylation embedded in extensive global hypomethylation. In contrast to the widely reported DNA hypermethylation of promoter-associated CpG islands (CGIs) in cancer, hypermethylated sites in MM as compared to normal plasma cells were located outside CpG islands and were unexpectedly associated with intronic enhancer regions active in normal B cells. Both RNA-seq and in vitro reporter assays indicated that enhancer hypermethylation is globally associated with downregulation of its host genes. ChIP-seq and DNAseI-seq further revealed that DNA hypermethylation in these regions was related to enhancer decommissioning. Hypermethylated enhancer regions overlap with binding sites of B-cell specific transcription factors (TFs) and the degree of enhancer methylation inversely correlated with expression levels of these TFs in MM. Furthermore, hypermethylated regions in MM were methylated in stem cells and gradually became demethylated during normal B-cell differentiation suggesting that MM cells reacquire epigenetic features of undifferentiated cells upon loss of expression of B-cell specific TFs. Overall, we have identified DNA hypermethylation of developmentally-regulated enhancers as a new type of epigenetic modification associated with the pathogenesis of MM. Disclosures No relevant conflicts of interest to declare.

scholarly journals Ticagrelor Modulates Proliferation in Multiple Myeloma Via P1 and P2 Receptor-Mediated Mechanisms

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5694-5694
Author(s):  
Elan Meltzer ◽  
Aranzazu Mediero ◽  
Carl Whatling ◽  
Jeffrey S Berger ◽  
Bruce Cronstein
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Research Funding ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Bone Destruction ◽  
Extracellular Adenosine ◽  
Myeloma Cells ◽  
Platelet Releasate

Abstract Background:Multiple Myeloma (MM) is a hematologic malignancy involving uncontrolled proliferation of plasma cells and is particularly trophic to bone where it induces osteoclast-mediated bone destruction. Ticagrelor is a platelet inhibitor that blocks P2Y12 receptors and inhibits ENT1-mediated adenosine uptake, thereby increasing extracellular adenosine, which activates P1 receptors. Prior studies demonstrate that ticagrelor increases life span in a murine model of MM via its effect on extracellular adenosine. Prior studies also demonstrate an increase in proliferation, in vitro, and tumor growth, in vivo, of MM cells in the presence of platelet releasate. Ticagrelor blocks in vitro platelet-stimulated myeloma proliferation, suggesting a positive relationship and interaction between active platelets and multiple myeloma. We therefore determined whether the effect of ticagrelor on myeloma cells was mediated by extra-cellular adenosine or/and inhibition of platelet function. Methods:Human primary myeloma cells (KMS) were incubated with ticagrelor (10-9-10-4 M) in the presence of 5ng/ml IL-6 in the absence/presence of an A2AR antagonist (ZM241385 10-6M) and platelets (1:500 myeloma cell:platelets). In other experiments MM cells were incubated in the presence of platelet releasate, releasate from platelets treated with ticagrelor, or ticagrelor alone. Proliferation was assayed by Cell Titer MTS assay (Promega). Results: Ticagrelor inhibited MM cell proliferation by 20% (p<0.0001, IC50=0.5µM). This effect was abrogated by ZM241385 (48±6% increased vs. ticagrelor, p<0.0001). Platelet releasate increased MM proliferation by 33±6% (p<0.05) and ticagrelor inhibited the effect of platelet releasate on MM cell proliferation (IC50=0.12µM). Conclusions:These results suggest that ticagrelor inhibits proliferation of malignant plasma cells by a mechanism dependent on both adenosine A2A and platelet P2Y12 receptors. Moreover, platelet releasate intensifies proliferation, and this effect is reversed when the P2Y12 receptor is blocked by ticagrelor. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Meltzer: NIH: Research Funding; Celgene: Research Funding; AstraZeneca: Research Funding. Mediero:AstraZeneca: Research Funding; Celgene: Research Funding; NIH: Research Funding. Whatling:AstraZeneca: Employment. Berger:Merck: Membership on an entity's Board of Directors or advisory committees; AZ: Research Funding. Cronstein:AstraZeneca: Consultancy, Research Funding; CanFite: Equity Ownership; Gizmo Therapeutics: Consultancy; Eli Lilly & Co.: Consultancy; NIH: Research Funding; Celgene: Research Funding.

scholarly journals Influence of gut microbiome on multiple myeloma: friend or foe?

2020 ◽  
Vol 8 (1) ◽  
pp. e000576
Author(s):  
Nausheen Ahmed ◽  
Mahmoud Ghannoum ◽  
Molly Gallogly ◽  
Marcos de Lima ◽  
Ehsan Malek
Keyword(s):  
Multiple Myeloma ◽  
Gut Microbiome ◽  
Monoclonal Gammopathy ◽  
Potential Role ◽  
Plasma Cells ◽  
Innate Immune ◽  
Factors Affecting ◽  
Underlying Mechanisms ◽  
Over Time

Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells, which typically evolves over time from its precursor, monoclonal gammopathy of undetermined significance. While the underlying mechanisms of this evolution remain elusive, immunomodulatory factors affecting the bone marrow (BM) microenvironment are suspected to play a role. There is an increasing evidence that the gut microbiome exerts an influence on its host’s adaptive and innate immune systems, inflammatory pathways and the BM microenvironment. Dysbiosis, therefore, may impact tumorigenesis in MM. This article gives an overview of potential mechanisms by which the microbiome may influence the pathogenesis of MM, MM patients’ responses to treatment and toxicities experienced by MM patients undergoing autologous transplant. It also discusses the potential role of the mycobiome in MM, a less studied component of the microbiome.

Impact of Natural Dietary Agents on Multiple Myeloma Prevention and Treatment: Molecular Insights and Potential for Clinical Translation

2020 ◽  
Vol 27 (2) ◽  
pp. 187-215 ◽  
Author(s):  
Lavinia Raimondi ◽  
Angela De Luca ◽  
Gianluca Giavaresi ◽  
Agnese Barone ◽  
Pierosandro Tagliaferri ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Multiple Myeloma ◽  
Natural Products ◽  
Bone Disease ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Signal Transduction Pathways ◽  
Pharmacologically Active ◽  
Dietary Agents

: Chemoprevention is based on the use of non-toxic, pharmacologically active agents to prevent tumor progression. In this regard, natural dietary agents have been described by the most recent literature as promising tools for controlling onset and progression of malignancies. Extensive research has been so far performed to shed light on the effects of natural products on tumor growth and survival, disclosing the most relevant signal transduction pathways targeted by such compounds. Overall, anti-inflammatory, anti-oxidant and cytotoxic effects of dietary agents on tumor cells are supported either by results from epidemiological or animal studies and even by clinical trials. : Multiple myeloma is a hematologic malignancy characterized by abnormal proliferation of bone marrow plasma cells and subsequent hypercalcemia, renal dysfunction, anemia, or bone disease, which remains incurable despite novel emerging therapeutic strategies. Notably, increasing evidence supports the capability of dietary natural compounds to antagonize multiple myeloma growth in preclinical models of the disease, underscoring their potential as candidate anti-cancer agents. : In this review, we aim at summarizing findings on the anti-tumor activity of dietary natural products, focusing on their molecular mechanisms, which include inhibition of oncogenic signal transduction pathways and/or epigenetic modulating effects, along with their potential clinical applications against multiple myeloma and its related bone disease.

scholarly journals Bioactive Compounds from Herbal Medicine Targeting Multiple Myeloma

2021 ◽  
Vol 11 (10) ◽  
pp. 4451
Author(s):  
Coralia Cotoraci ◽  
Alina Ciceu ◽  
Alciona Sasu ◽  
Eftimie Miutescu ◽  
Anca Hermenean
Keyword(s):  
Multiple Myeloma ◽  
Survival Rate ◽  
Plasma Cells ◽  
Inhibition Of Proliferation ◽  
In Vivo Experiments ◽  
Clonal Proliferation ◽  
Hematological Cancers ◽  
Monoclonal Proteins

Multiple myeloma (MM) is one of the most widespread hematological cancers. It is characterized by a clonal proliferation of malignant plasma cells in the bone marrow and by the overproduction of monoclonal proteins. In recent years, the survival rate of patients with multiple myeloma has increased significantly due to the use of transplanted stem cells and of the new therapeutic agents that have significantly increased the survival rate, but it still cannot be completely cured and therefore the development of new therapeutic products is needed. Moreover, many patients have various side effects and face the development of drug resistance to current therapies. The purpose of this review is to highlight the bioactive active compounds (flavonoids) and herbal extracts which target dysregulated signaling pathway in MM, assessed by in vitro and in vivo experiments or clinical studies, in order to explore their healing potential targeting multiple myeloma. Mechanistically, they demonstrated the ability to promote cell cycle blockage and apoptosis or autophagy in cancer cells, as well as inhibition of proliferation/migration/tumor progression, inhibition of angiogenesis in the tumor vascular network. Current research provides valuable new information about the ability of flavonoids to enhance the apoptotic effects of antineoplastic drugs, thus providing viable therapeutic options based on combining conventional and non-conventional therapies in MM therapeutic protocols.

scholarly journals Belantamab Mafodotin to Treat Multiple Myeloma: A Comprehensive Review of Disease, Drug Efficacy and Side Effects

2021 ◽  
Vol 28 (1) ◽  
pp. 640-660
Author(s):  
Grace Lassiter ◽  
Cole Bergeron ◽  
Ryan Guedry ◽  
Julia Cucarola ◽  
Adam M. Kaye ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Drug Efficacy ◽  
Treatment Modalities ◽  
Blurred Vision ◽  
Refractory Multiple Myeloma ◽  
Therapeutic Modalities ◽  
Clonal Proliferation ◽  
Refractory State

Multiple myeloma (MM) is a hematologic malignancy characterized by excessive clonal proliferation of plasma cells. The treatment of multiple myeloma presents a variety of unique challenges due to the complex molecular pathophysiology and incurable status of the disease at this time. Given that MM is the second most common blood cancer with a characteristic and unavoidable relapse/refractory state during the course of the disease, the development of new therapeutic modalities is crucial. Belantamab mafodotin (belamaf, GSK2857916) is a first-in-class therapeutic, indicated for patients who have previously attempted four other treatments, including an anti-CD38 monoclonal antibody, a proteosome inhibitor, and an immunomodulatory agent. In November 2017, the FDA designated belamaf as a breakthrough therapy for heavily pretreated patients with relapsed/refractory multiple myeloma. In August 2020, the FDA granted accelerated approval as a monotherapy for relapsed or treatment-refractory multiple myeloma. The drug was also approved in the EU for this indication in late August 2020. Of note, belamaf is associated with the following adverse events: decreased platelets, corneal disease, decreased or blurred vision, anemia, infusion-related reactions, pyrexia, and fetal risk, among others. Further studies are necessary to evaluate efficacy in comparison to other standard treatment modalities and as future drugs in this class are developed.

scholarly journals The oxidative stress response regulates DKK1 expression through the JNK signaling cascade in multiple myeloma plasma cells

Blood ◽  
2007 ◽  
Vol 109 (10) ◽  
pp. 4470-4477 ◽  
Author(s):  
Simona Colla ◽  
Fenghuang Zhan ◽  
Wei Xiong ◽  
Xiaosong Wu ◽  
Hongwei Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Multiple Myeloma ◽  
Wnt Signaling ◽  
Plasma Cells ◽  
Cell Types ◽  
Signaling Cascade ◽  
Jnk Pathway ◽  
Jnk Signaling ◽  
Dkk1 Expression

Abstract Multiple myeloma (MM) plasma cells, but not those from healthy donors and patients with monoclonal gammopathy of undetermined significance or other plasma cell dyscrasias involving the bone marrow, express the Wnt-signaling antagonist DKK1. We previously reported that secretion of DKK1 by MM cells likely contributes to osteolytic lesions in this disease by inhibiting Wnt signaling, which is essential for osteoblast differentiation and survival. The mechanisms responsible for activation and regulation of DKK1 expression in MM are not known. Herein, we could trace DKK1 expression changes in MM cells to perturbations in the JNK signaling cascade, which is differentially modulated through oxidative stress and interactions between MM cells with osteoclasts in vitro. Despite its role as a tumor suppressor and mediator of apoptosis in other cell types including osteoblasts, our data suggest that DKK1, a stress-responsive gene in MM, does not mediate apoptotic signaling, is not activated by TP53, and its forced overexpression could not inhibit cell growth or sensitize MM cells to apoptosis following treatment with thalidomide or lenalidomide. We conclude that specific strategies to modulate persistent activation of the JNK pathway may be beneficial in preventing disease progression and treating myeloma-associated bone disease by inhibiting DKK1 expression.

scholarly journals IL-32 is a metabolic regulator promoting survival and proliferation of malignant plasma cells

2021 ◽  
Author(s):  
Kristin Roseth Aass ◽  
Robin Mjelle ◽  
Martin H. Kastnes ◽  
Synne S. Tryggestad ◽  
Luca M. van den Brink ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Oxidative Phosphorylation ◽  
Plasma Cells ◽  
Inflammatory Diseases ◽  
Mitochondrial Respiratory Chain ◽  
Gene Signature ◽  
Growth And Survival ◽  
Novel Concept

AbstractIL-32 is a non-classical cytokine expressed in cancers, inflammatory diseases and infections. IL-32 can have both extracellular and intracellular functions, and its receptor is not identified. We here demonstrate that endogenously expressed, intracellular IL-32 binds to components of the mitochondrial respiratory chain and promotes oxidative phosphorylation. Knocking out IL-32 in malignant plasma cells significantly reduced survival and proliferation in vitro and in vivo. High throughput transcriptomic and MS-metabolomic profiling of IL-32 KO cells revealed that loss of IL-32 leads to profound perturbations in metabolic pathways, with accumulation of lipids, pyruvate precursors and citrate, indicative of reduced mitochondrial function. IL-32 is expressed in a subgroup of multiple myeloma patients with an inferior prognosis. Primary myeloma cells expressing IL-32 were characterized by a plasma cell gene signature associated with immune activation, proliferation and oxidative phosphorylation. We propose a novel concept for regulation of metabolism by an intracellular cytokine and identify IL-32 as an endogenous growth and survival factor for malignant plasma cells. IL-32 is a potential prognostic biomarker and a treatment target in multiple myeloma.

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