Pathology Of Multiple Myeloma Research Articles

Liposomes have a direct effect on multiple myeloma: a Mendelian randomization study.

Multiple myeloma (MM), a malignant disease of plasma cells originating in the bone marrow, is influenced significantly by genetic factors. Although plasma liposomes have been linked to MM, the nature of their potential causal relationship remains to be elucidated. This study aims to explore this relationship using Mendelian randomization (MR) analysis. Liposome-associated genetic instrumental variables (IVs) were identified from plasma lipidomics data of 7,174 Finnish individuals within a Genome-Wide Association Study (GWAS) pooled database. A MM pooled dataset was sourced from a GWAS meta-analysis encompassing 150,797 individuals, including 598 MM patients and 218,194 controls. These IVs underwent MR analysis, adhering to strict criteria for correlation, independence, and the exclusion of confounders. The inverse variance weighted (IVW) method, MR-Egger method, weighted median (WM) method, and simple median were utilized for MR analysis assessment, alongside Cochran's Q test, MR-Egger intercept, MR-Pleiotropy Residual Sum and Outlier (MR-RESSO) method, and leave-one-out analysis for evaluating heterogeneity, multiplicity, and instrumental bias. The study identified 88 significant, independent single nucleotide polymorphisms (SNPs) as IVs for MR analysis, each with an F-statistic value above 10, indicating robustness against weak instrument bias. IVW analysis revealed associations between six plasma liposome components and MM risk (p < 0.05). Phosphatidylinositol (16:0_18:1) serum levels (odds ratio [OR] = 1.769, 95% confidence interval [CI]: 1.132-2.763, p = 0.012) and triacylglycerol (56:4) levels (p = 0.026, OR = 1.417, 95% CI: 1.042-1.926) were positively correlated with the risk of multiple myeloma development. Phosphatidylethanolamine (18:0_20:4) (p = 0.004, 95% CI: 0.621-0.916, OR = 0.754), phosphatidylcholine (18:2_20:4) (p = 0.004, OR = 0.680, 95% CI: 0.519-0.889), sterol ester (27:1/18:3) levels (p = 0.013, OR = 0.677, 95% CI: 0.498-0.922), and phosphatidylcholine (O-18:2_20:4) levels (OR = 0.710, 95% CI: 0.517-0.913, p = 0.033) were negatively associated with the risk of developing multiple myeloma. The Cochran's Q test did not detect statistical method heterogeneity, nor did the MR-RESSO test or the MR-Egger intercept detect horizontal pleiotropy; leave-one-out analyses confirmed the absence of bias from individual SNPs. Our findings suggest a complex relationship between plasma liposome components and MM risk. Elevated serum levels of triacylglycerol and phosphatidylinositol are positively associated with MM risk, while certain phospholipids and sterol esters offer a protective effect. This study provides valuable insights into the clinical relevance of liposomes in the pathology of multiple myeloma.

Synergistic Effects of Type I PRMT1 and Type II PRMT5 Inhibitors Against Multiple Myeloma

Multiple myeloma (MM) is a plasma cell malignancy characterized by the extensive expansion of monoclonal aberrant plasma cells in the bone marrow and the second most prevalent hematological malignancies worldwide. Despite the promising outcomes of advanced therapies, relapsed/refractory (RR) diseases remain incurable, highlighting an unmet clinical need to identify novel therapeutic targets. An emerging field of investigation is the role of aberrant post-translational modifications in multiple myeloma pathology. Arginine methylation is one of the most predominant post-translational modifications in cells, catalyzed by protein arginine methyltransferases (PRMTs) that plays a crucial role in multiple cellular processes. Type I PRMTs catalyze mono- (MMA) and asymmetric demethylation (ADMA) of arginine; Type II PRMTs catalyze mono- and symmetric demethylation (SDMA) of arginine on proteins; Type III PRMT mediates MMA only. Aberrant expression of PRMTs is strongly associated with poor prognosis of solid cancers and hematologic malignancies. Recently, we identified PRMT1 as a novel therapeutic vulnerability in MM cells. Among PRMTs, PRMT1 is the highest expressed gene in MM cell lines and patient cells. The elevation of PRMT1 expression is strongly associated with relapsed/refractory patients and poor clinical outcomes. Deletion of PRMT1 and suppression of the PRMT1's enzymatic activity exhibited a strong anti-MM in vitro via suppressing cell cycle and elevating the apoptosis. We also found that inhibition of PRMT1 boosts the T cell activation in the co-culture setup, indicating a potential enhancement of immunotherapy. Using a subcutaneous xenograft model, we showed that suppressing PRTM1 in vivo by either genetic or pharmaceutical approaches robustly inhibits MM tumor growth and extends survival of tumor-bearing mice. Our findings demonstrated that PRMT1 is indispensable in MM. PRMT5, a PRMT type II, is prognostically relevant and a known druggable target in MM. PRMT1 and PRMT5 inversely regulate post-transcription and have been implicated in human cancers. Recent studies in solid tumor showed a strong anti-tumor effect in vivo using the combinational inhibition of PRMT1 and PRMT5. We hypothesize that PRMT1 and PRMT5 might have a complementary function in MM cells. The combinational inhibition PRMT1 and PRTM5 will exhibit a synergistic anti-MM effect. To address this hypothesis, we treated MM cell lines with two clinical trial inhibitors: GSK3368715 (GSK) and EPZ 015666 (EPZ), suppressing PRMT type I and type II inhibitor, respectively. We first performed dose-dependent cell viability inhibition and selected effective doses for drug combination treatments in three different MM cell lines. The combination of GSK and EPZ demonstrated a strong synergistic effect in suppressing the viability of MM cells. Using the SynergyFinder algorithm, we found that the synergistic indexes (&amp;gt;10, synergism) for 3 MM cell lines JJN3, MM1S, and KMS11 were 33.5, 32.8, and 14.3, respectively. We next assessed the effects of combined treatment on the cell cycle and apoptosis of MM cells. We found that combination of GSK and EPZ strikingly elevated the apoptosis and suppressed cell cycle of MM cell lines compared single treatment and untreated control. Intriguingly, the combination treatment of two inhibitors significantly decreased MMA, SDMA, and ADMA, suggesting a robust suppression of global arginine methylation. Of note, we found a similar anti-MM effect when treating bortezomib-resistant MM cells with GSK and EPZ, indicating that PRMT type I and type II inhibitors potentially have a substantial clinical impact on relapsed MM. Of note, the same dose of GSK and EPZ that exhibits the synergistic anti-MM effect, didn't suppress the viability of healthy peripheral blood cells. In summary, our preliminary data suggest that suppression of both PRMT type I and type II might provide a potential effective combination treatment for both newly diagnosed and relapsed MM patients. We're currently investigating the underling mechanisms of how PRMTs regulate MM pathology and validating the in vivo efficacy of combination treatment using patient-derived xenograft.

DEVELOPMENT OF MULTIPLE MYELOMA CELL LINES WITH HIGH EXPRESSION OF HEPATOCYTE GROWTH FACTOR

Objective:&#x0D; To determine the overexpress HGF gene in non HGF producing humane myeloma cell lines (INA-6).&#x0D; Materials and Methods:&#x0D; In this study, retroviral- expression constructs were designed and constructed. The sequence of the cloned fragments in the vector constructs was determined and the effect of construct was examined using qRT-PCR and Western blot analysis. At department of cancer research &amp; molecular medicine, norwegien university of science &amp; technology, Trondheim Norway, in June 2016 to April 2018.&#x0D; Results:&#x0D; We established expression constructs based on HGF mRNA sequence. The HGF non producing human myeloma cell line INA-6 transduced with lentiviral HGF-overexpression transduction particles, were analyzed for their effect on the HGF gene expression. HGF overexpression was analyzed both at mRNA level and protein levels. Two myeloma cell line INA-6 HGF-1 and INA-6HGF-2 showed significant over expression of HGF mRNA and protein.&#x0D; Conclusion:&#x0D; In conclusion, the HGF overexpression cell lines can be used as tissue culture models to investigate the role of HGF protein in pathology of multiple myeloma.

ESTABLISHMENT OF MULTIPLE MYELOMA CELL LINES WITH REDUCED EXPRESSION OF HEPATOCYTE GROWTH FACTOR USING RNAI APPROACH

Objective: To establish the gene knockdown system (RNAi) using different Multiple Myeloma Cell lines (MMCL). Material and Methods: RNAi is generally used in biomedical research to study the outcome of knockdown of gene expression. In this research, retroviral-shRNA expression constructs based on micro RNA-adapted short hairpin RNA (sh RNA mir) were designed and constructed. The sequence of the cloned fragments in the vector constructs was determined, and the effect of constructs in MMCLs was examined using qRT-PCR and Western blot analysis. Results: In this work, we established a method for making retroviral-shRNA expression constructs based on micro RNA-adapted short hairpin RNA (sh RNA mir) design. The HGF producing human myeloma cell line JJN-3 transduced with lentiviral HGF-shRNA transduction particles were analyzed for their effect on the HGF gene expression. HGF knockdown MMCL was analyzed both at mRNA level and protein levels. Two out of five clones of myeloma cell line JJN-3 (JJN3-sh3308 and JJN3-sh47137) were transduced with lentiviral HGF–shRNA transduction particles were showing 50-60 % knockdown in their HGF mRNA and protein expression. Conclusion: HGF knockdown cell lines can be used as tissue culture models to investigate the role of HGF protein in the pathology of multiple myeloma. Further, the retroviral-HGF-shRNA expression constructs can study HGF response in various multiple myeloma via gene knockdown studies.

Cardamonin exerts potent activity against multiple myeloma through blockade of NF-κB pathway in vitro

NF-κB plays a major role in the pathology of multiple myeloma. Here, we intended to investigate the regulating effect of cardamonin on NF-κB in myeloma cells. We found for the first time that cardamonin suppressed viability and induced apoptosis of myeloma cells. Cardamonin activated caspase-3 and PARP and suppressed the expression of various anti-apoptotic proteins. We discovered that NF-κB was repressed by cardamonin through suppression of IKK expression and IκBα phosphorylation. Furthermore, the expression of NF-κB-regulated gene products ICAM-1, COX-2 and VEGF was down-regulated by cardamonin. These results suggest that cardamonin blocks NF-κB pathway in human multiple myeloma cells.

Multiple Myeloma and Related Disorders,

This is an excellent monograph in which the senior author-editor achieves his primary aim (as stated in the preface) of providing newer information and concepts as well as of emphasizing older valuable landmarks. The seven chapters are written by the two authors-editors and other authorities in the field and deal with the following topics: pathology of multiple myeloma, the myeloma cell, experimental plasma cell tumors, antigen binding M-components, benign monoclonal gammopathies, immunologic deficiency syndromes, and amyloidosis. In putting together the conceptual design of each chapter, the authors draw on their own vast experience, particularly where necessary to fill in gaps in knowledge. The various authors do not hesitate to go to the edge of current knowledge to provide useful concepts regarding the unknown, tentative though they must be. Another advantage is the relating of concepts of mechanisms involved in myeloma and similar disorders to other phenomena, such as autoimmunity, cancer,