scholarly journals Role of 1q21 in Multiple Myeloma: From Pathogenesis to Possible Therapeutic Targets

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1360
Author(s):  
Jessica Burroughs Garcìa ◽  
Rosa Alba Eufemiese ◽  
Paola Storti ◽  
Gabriella Sammarelli ◽  
Luisa Craviotto ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
De Novo ◽  
Current Knowledge ◽  
Therapeutic Targets ◽  
Poor Response ◽  
Signal Pathway ◽  
Pathological Features ◽  
Therapeutic Approaches

Multiple myeloma (MM) is characterized by an accumulation of malignant plasma cells (PCs) in the bone marrow (BM). The amplification of 1q21 is one of the most common cytogenetic abnormalities occurring in around 40% of de novo patients and 70% of relapsed/refractory MM. Patients with this unfavorable cytogenetic abnormality are considered to be high risk with a poor response to standard therapies. The gene(s) driving amplification of the 1q21 amplicon has not been fully studied. A number of clear candidates are under investigation, and some of them (IL6R, ILF2, MCL-1, CKS1B and BCL9) have been recently proposed to be potential drivers of this region. However, much remains to be learned about the biology of the genes driving the disease progression in MM patients with 1q21 amp. Understanding the mechanisms of these genes is important for the development of effective targeted therapeutic approaches to treat these patients for whom effective therapies are currently lacking. In this paper, we review the current knowledge about the pathological features, the mechanism of 1q21 amplification, and the signal pathway of the most relevant candidate genes that have been suggested as possible therapeutic targets for the 1q21 amplicon.

scholarly journals Glioma Stem Cells: Signaling, Microenvironment, and Therapy

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Brandon D. Liebelt ◽  
Takashi Shingu ◽  
Xin Zhou ◽  
Jiangong Ren ◽  
Seul A. Shin ◽  
...  
Keyword(s):  
De Novo ◽  
Current Knowledge ◽  
Primary Brain Tumor ◽  
Tumor Formation ◽  
Therapeutic Approaches ◽  
Microenvironmental Factors ◽  
Xenograft Models ◽  
And Function ◽  
Vascular Formation

Glioblastoma remains the most common and devastating primary brain tumor despite maximal therapy with surgery, chemotherapy, and radiation. The glioma stem cell (GSC) subpopulation has been identified in glioblastoma and likely plays a key role in resistance of these tumors to conventional therapies as well as recurrent disease. GSCs are capable of self-renewal and differentiation; glioblastoma-derived GSCs are capable ofde novotumor formation when implanted in xenograft models. Further, GSCs possess unique surface markers, modulate characteristic signaling pathways to promote tumorigenesis, and play key roles in glioma vascular formation. These features, in addition to microenvironmental factors, present possible targets for specifically directing therapy against the GSC population within glioblastoma. In this review, the authors summarize the current knowledge of GSC biology and function and the role of GSCs in new vascular formation within glioblastoma and discuss potential therapeutic approaches to target GSCs.

scholarly journals Differential epigenetic regulation between the alternative promoters, PRDM1α and PRDM1β, of the tumour suppressor gene PRDM1 in human multiple myeloma cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Raquel Romero-García ◽  
Laura Gómez-Jaramillo ◽  
Rosa María Mateos ◽  
Gema Jiménez-Gómez ◽  
Nuria Pedreño-Horrillo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Plasma Cells ◽  
Regulatory Elements ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Alternative Promoters ◽  
Therapeutic Approaches ◽  
Human Multiple Myeloma

Abstract Multiple myeloma (MM) is a B-cell neoplasm that is characterized by the accumulation of malignant plasma cells in the bone marrow. The transcription factor PRDM1 is a master regulator of plasma cell development and is considered to be an oncosuppressor in several lymphoid neoplasms. The PRDM1β isoform is an alternative promoter of the PRDM1 gene that may interfere with the normal role of the PRDM1α isoform. To explain the induction of the PRDM1β isoform in MM and to offer potential therapeutic strategies to modulate its expression, we characterized the cis regulatory elements and epigenetic status of its promoter. We observed unexpected patterns of hypermethylation and hypomethylation at the PRDM1α and PRDM1β promoters, respectively, and prominent H3K4me1 and H3K9me2 enrichment at the PRDM1β promoter in non-expressing cell lines compared to PRDM1β-expressing cell lines. After treatment with drugs that inhibit DNA methylation, we were able to modify the activity of the PRDM1β promoter but not that of the PRDM1α promoter. Epigenetic drugs may offer the ability to control the expression of the PRDM1α/PRDM1β promoters as components of novel therapeutic approaches.

scholarly journals Roles of miRNA dysregulation in the pathogenesis of multiple myeloma

2021 ◽  
Author(s):  
Dan Chen ◽  
Xinhong Yang ◽  
Min Liu ◽  
Zhihua Zhang ◽  
Enhong Xing
Keyword(s):  
Multiple Myeloma ◽  
Malignant Disease ◽  
Plasma Cells ◽  
Current Knowledge ◽  
Proteasome Inhibitors ◽  
Therapeutic Approaches ◽  
Regulate Gene Expression ◽  
The Past ◽  
Mirna Deregulation ◽  
Posttranscriptional Level

AbstractMultiple myeloma (MM) is a malignant disease of plasma cells with complex pathology, causing significant morbidity due to its end-organ destruction. The outcomes of patients with myeloma have significantly improved in the past couple of decades with the introduction of novel agents, such as proteasome inhibitors, immunomodulators, and monoclonal antibodies. However, MM remains incurable and presents considerable individual heterogeneity. MicroRNAs (miRNAs) are short, endogenous noncoding RNAs of 19–22 nucleotides that regulate gene expression at the posttranscriptional level. Numerous studies have shown that miRNA deregulation is closely related to MM pathology, including tumor initiation, progression, metastasis, prognosis, and drug response, which make the complicated miRNA network an attractive and marvelous area of investigation for novel anti-MM therapeutic approaches. Herein, we mainly summarized the current knowledge on the roles of miRNAs, which are of great significance in regulating pathological factors involved in MM progressions, such as bone marrow microenvironment, methylation, immune regulation, genomic instability, and drug resistance. Meanwhile, their potential as novel prognostic biomarkers and therapeutic targets was also discussed.

scholarly journals Regulatory T Cell-Enhancing Therapies to Treat Atherosclerosis

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 723
Author(s):  
Hafid Ait-Oufella ◽  
Jean-Rémi Lavillegrand ◽  
Alain Tedgui
Keyword(s):  
T Cell ◽  
Current Knowledge ◽  
Experimental Studies ◽  
Therapeutic Approaches ◽  
Coronary Patients ◽  
Cell Subpopulations ◽  
Atherosclerotic Process ◽  
T Cell Subpopulations ◽  
Disease Analysis

Experimental studies have provided strong evidence that chronic inflammation triggered by the sub-endothelial accumulation of cholesterol-rich lipoproteins in arteries is essential in the initiation and progression of atherosclerosis. Recent clinical trials highlighting the efficacy of anti-inflammatory therapies in coronary patients have confirmed that this is also true in humans Monocytes/macrophages are central cells in the atherosclerotic process, but adaptive immunity, through B and T lymphocytes, as well as dendritic cells, also modulates the progression of the disease. Analysis of the role of different T cell subpopulations in murine models of atherosclerosis identified effector Th1 cells as proatherogenic, whereas regulatory T cells (Tregs) have been shown to protect against atherosclerosis. For these reasons, better understanding of how Tregs influence the atherosclerotic process is believed to provide novel Treg-targeted therapies to combat atherosclerosis. This review article summarizes current knowledge about the role of Tregs in atherosclerosis and discusses ways to enhance their function as novel immunomodulatory therapeutic approaches against cardiovascular disease.

scholarly journals Role of Aiolos and Ikaros in the Antitumor and Immunomodulatory Activity of IMiDs in Multiple Myeloma: Better to Lose Than to Find Them

2021 ◽  
Vol 22 (3) ◽  
pp. 1103
Author(s):  
Marco Cippitelli ◽  
Helena Stabile ◽  
Andrea Kosta ◽  
Sara Petillo ◽  
Angela Gismondi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Immunomodulatory Activity ◽  
Cancer Cell Growth ◽  
Cytotoxic Effects ◽  
Growth And Survival ◽  
Therapeutic Implications ◽  
Development And Differentiation ◽  
Innate Lymphocytes

The Ikaros zing-finger family transcription factors (IKZF TFs) are important regulators of lymphocyte development and differentiation and are also highly expressed in B cell malignancies, including Multiple Myeloma (MM), where they are required for cancer cell growth and survival. Moreover, IKZF TFs negatively control the functional properties of many immune cells. Thus, the targeting of these proteins has relevant therapeutic implications in cancer. Indeed, accumulating evidence demonstrated that downregulation of Ikaros and Aiolos, two members of the IKZF family, in malignant plasma cells as well as in adaptative and innate lymphocytes, is key for the anti-myeloma activity of Immunomodulatory drugs (IMiDs). This review is focused on IKZF TF-related pathways in MM. In particular, we will address how the depletion of IKZF TFs exerts cytotoxic effects on MM cells, by reducing their survival and proliferation, and concomitantly potentiates the antitumor immune response, thus contributing to therapeutic efficacy of IMiDs, a cornerstone in the treatment of this neoplasia.

scholarly journals Targeting Multiple-Myeloma-Induced Immune Dysfunction to Improve Immunotherapy Outcomes

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Sergio Rutella ◽  
Franco Locatelli
Keyword(s):  
Multiple Myeloma ◽  
De Novo ◽  
Current Knowledge ◽  
Cell Immunity ◽  
Benign Monoclonal Gammopathy ◽  
Molecular Determinants ◽  
Clinical Responses ◽  
Cause Of Failure ◽  
Immune Defects ◽  
Cell Malignancy

Multiple myeloma (MM) is a plasma cell malignancy associated with high levels of monoclonal (M) protein in the blood and/or serum. MM can occurde novoor evolve from benign monoclonal gammopathy of undetermined significance (MGUS). Current translational research into MM focuses on the development of combination therapies directed against molecularly defined targets and that are aimed at achieving durable clinical responses. MM cells have a unique ability to evade immunosurveillance through several mechanisms including, among others, expansion of regulatory T cells (Treg), reduced T-cell cytotoxic activity and responsiveness to IL-2, defects in B-cell immunity, and induction of dendritic cell (DC) dysfunction. Immune defects could be a major cause of failure of the recent immunotherapy trials in MM. This article summarizes our current knowledge on the molecular determinants of immune evasion in patients with MM and highlights how these pathways can be targeted to improve patients’ clinical outcome.

scholarly journals The Role of epigenetic modifications of DNA and histones in the treatment of oncohematological diseases

2021 ◽  
Vol 66 (2) ◽  
pp. 263-279
Author(s):  
D. V. Karpenko ◽  
N. A. Petinati ◽  
N. J. Drize ◽  
A. E. Bigildeev
Keyword(s):  
Clinical Trial ◽  
Cytosine Methylation ◽  
Current Knowledge ◽  
Hypomethylating Agents ◽  
Epigenetic Change ◽  
Therapeutic Approaches ◽  
Enzymatic Machinery ◽  
Key Pathways ◽  
Dna Cytosine Methylation

Introduction. Current knowledge of tumour biology attests a dual genetic and epigenetic nature of cancer cell abnormalities. Tumour epigenetics research provided insights into the key pathways mediating oncogenesis and facilitated novel epigenetic therapies.Aim — an overview of intricate involvement of epigenetic change in haematological morbidity and current therapeutic approaches to target the related mechanisms.Main findings. We review the best known epigenetic marks in tumour cells, e.g. DNA cytosine methylation, methylation and acetylation of histone proteins, the underlying enzymatic machinery and its role in oncogenesis. The epigenetic profile-changing drugs are described, including DNA hypomethylating agents, histone deacetylase and methylase inhibitors. A particular focus is made on substances currently approved in haematological therapy or undergoing clinical trial phases for future clinical availability.

SUCCESSFUL MANAGEMENT OF SPHENOID RELAPSE OF MULTIPLE MYELOMA WITH RADIATION THERAPY: A CASE REPORT

2021 ◽  
pp. 1-2
Author(s):  
A. Bazine ◽  
M. Torreis ◽  
M. Elmarjany ◽  
M. Benlemlih ◽  
A. Maghous ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Radiation Therapy ◽  
Case Report ◽  
Skull Base ◽  
Plasma Cells ◽  
Complete Disappearance ◽  
Successful Management ◽  
Shed Light

Multiple myeloma (MM) is typically characterized by neoplastic proliferation of plasma cells in the bone marrow and can result in extensive skeletal destruction. Involvement of skull base is extremely rare, especially sphenoid bone. We report in this work the case of a 62-year-old woman, who presented with a sphenoid relapse of multiple myeloma treated with radiation therapy, with signicant clinical improvement and almost complete disappearance of the sphenoid metastasis. We shed light, through this case, on the rarity of sphenoid metastases in multiple myeloma and on the role of radiotherapy in the management of this type of location.

scholarly journals Extracellular Chaperones as Novel Biomarkers of Overall Cancer Progression and Efficacy of Anticancer Therapy

2020 ◽  
Vol 10 (17) ◽  
pp. 6009
Author(s):  
Malgorzata Anna Krawczyk ◽  
Agata Pospieszynska ◽  
Małgorzata Styczewska ◽  
Ewa Bien ◽  
Sambor Sawicki ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Current Knowledge ◽  
Therapeutic Targets ◽  
Age Group ◽  
Cancer Management ◽  
Novel Biomarkers ◽  
Immune System Regulation ◽  
New Biomarkers ◽  
Shock Proteins

Exosomal heat shock proteins (Hsps) are involved in intercellular communication both in physiological and pathological conditions. They play a role in key processes of carcinogenesis including immune system regulation, cell differentiation, vascular homeostasis and metastasis formation. Thus, exosomal Hsps are emerging biomarkers of malignancies and possible therapeutic targets. Adolescents and young adults (AYAs) are patients aged 15–39 years. This age group, placed between pediatric and adult oncology, pose a particular challenge for cancer management. New biomarkers of cancer growth and progression as well as prognostic factors are desperately needed in AYAs. In this review, we attempted to summarize the current knowledge on the role of exosomal Hsps in selected solid tumors characteristic for the AYA population and/or associated with poor prognosis in this age group. These included malignant melanoma, brain tumors, and breast, colorectal, thyroid, hepatocellular, lung and gynecological tract carcinomas. The studies on exosomal Hsps in these tumors are limited; however; some have provided promising results. Although further research is needed, there is potential for future clinical applications of exosomal Hsps in AYA cancers, both as novel biomarkers of disease presence, progression or relapse, or as therapeutic targets or tools for drug delivery.

scholarly journals Role of microRNAs in Venous Thromboembolism

2020 ◽  
Vol 21 (7) ◽  
pp. 2602 ◽  
Author(s):  
Vânia M. Morelli ◽  
Sigrid K. Brækkan ◽  
John-Bjarne Hansen
Keyword(s):  
Venous Thromboembolism ◽  
Animal Models ◽  
Statistical Power ◽  
Current Knowledge ◽  
Thrombus Formation ◽  
Therapeutic Targets ◽  
Small Sample ◽  
Future Research ◽  
Gene Expressions

MicroRNAs (miRNAs) are non-coding RNAs that execute their function by targeted downregulation of gene expressions. There is growing evidence from epidemiological studies and animal models suggesting that the expression level of miRNAs is dysregulated in venous thromboembolism (VTE). In this review, we summarize the current knowledge on the role of miRNAs as biomarkers for VTE and provide general insight into research exploring the modulation of miRNA activity in animal models of venous thrombosis. Up to now, published studies have yielded inconsistent results on the role of miRNAs as biomarkers for VTE with most of the reports focused on diagnostic research. The limited statistical power of the individual studies, due to the small sample sizes, may substantially contribute to the poor reproducibility among studies. In animal models, over-expression or inhibition of some miRNAs appear to influence venous thrombus formation and resolution. However, there is an important gap in knowledge on the potential role of miRNAs as therapeutic targets in VTE. Future research involving large cohorts should be designed to clarify the clinical usefulness of miRNAs as biomarkers for VTE, and animal model studies should be pursued to unravel the role of miRNAs in the pathogenesis of VTE and their potential as therapeutic targets.

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