Current knowledge of Epigenetic Events in Multiple Myeloma

2021 ◽  
pp. 56-72
Author(s):  
Flodrova Pavla ◽  
Luzna Petra ◽  
Weiser-Drozdkova Denisa ◽  
Smesny Trtkova Katerina
Keyword(s):  
Multiple Myeloma ◽  
Current Knowledge ◽  
Epigenetic Events

scholarly journals Gain/Amplification of Chromosome Arm 1q21 in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 256
Author(s):  
Ichiro Hanamura
Keyword(s):  
Multiple Myeloma ◽  
Hematological Malignancy ◽  
Treatment Approach ◽  
Current Knowledge ◽  
Chromosome 1 ◽  
Plasma Cell Neoplasm ◽  
Chromosome Arm ◽  
Cell Neoplasm ◽  
Prognostic Implications ◽  
Tandem Duplications

Multiple myeloma (MM), a plasma cell neoplasm, is an incurable hematological malignancy characterized by complex genetic and prognostic heterogeneity. Gain or amplification of chromosome arm 1q21 (1q21+) is the most frequent adverse chromosomal aberration in MM, occurring in 40% of patients at diagnosis. It occurs in a subclone of the tumor as a secondary genomic event and is more amplified as the tumor progresses and a risk factor for the progression from smoldering multiple myeloma to MM. It can be divided into either 1q21 gain (3 copies) or 1q21 amplification (≥4 copies), and it has been suggested that the prognosis is worse in cases of amplification than gain. Trisomy of chromosome 1, jumping whole-arm translocations of chromosome1q, and tandem duplications lead to 1q21+ suggesting that its occurrence is not consistent at the genomic level. Many studies have reported that genes associated with the malignant phenotype of MM are situated on the 1q21 amplicon, including CKS1B, PSMD4, MCL1, ANP32E, and others. In this paper, we review the current knowledge regarding the clinical features, prognostic implications, and the speculated pathology of 1q21+ in MM, which can provide clues for an effective treatment approach to MM patients with 1q21+.

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 Natural Killer Cells in the Malignant Niche of Multiple Myeloma

2022 ◽  
Vol 12 ◽  
Author(s):  
Ondrej Venglar ◽  
Julio Rodriguez Bago ◽  
Benjamin Motais ◽  
Roman Hajek ◽  
Tomas Jelinek
Keyword(s):  
Multiple Myeloma ◽  
Nk Cells ◽  
Natural Killer ◽  
Defense Mechanisms ◽  
Hematological Malignancies ◽  
Cell Function ◽  
Nk Cell ◽  
Current Knowledge ◽  
Suppressor Activity ◽  
Infected Cells

Natural killer (NK) cells represent a subset of CD3- CD7+ CD56+/dim lymphocytes with cytotoxic and suppressor activity against virus-infected cells and cancer cells. The overall potential of NK cells has brought them to the spotlight of targeted immunotherapy in solid and hematological malignancies, including multiple myeloma (MM). Nonetheless, NK cells are subjected to a variety of cancer defense mechanisms, leading to impaired maturation, chemotaxis, target recognition, and killing. This review aims to summarize the available and most current knowledge about cancer-related impairment of NK cell function occurring in MM.

scholarly journals Long Non-Coding RNAs in Multiple Myeloma

2019 ◽  
Vol 5 (1) ◽  
pp. 13 ◽  
Author(s):  
Romana Butova ◽  
Petra Vychytilova-Faltejskova ◽  
Adela Souckova ◽  
Sabina Sevcikova ◽  
Roman Hajek
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Current Knowledge ◽  
Biological Processes ◽  
Cell Distribution ◽  
Rna Molecules ◽  
Non Coding Rna ◽  
Non Coding Rnas ◽  
New Treatment ◽  
Long Non Coding Rna

Multiple myeloma (MM) is the second most common hematooncological disease of malignant plasma cells in the bone marrow. While new treatment brought unprecedented increase of survival of patients, MM pathogenesis is yet to be clarified. Increasing evidence of expression of long non-coding RNA molecules (lncRNA) linked to development and progression of many tumors suggested their important role in tumorigenesis. To date, over 15,000 lncRNA molecules characterized by diversity of function and specificity of cell distribution were identified in the human genome. Due to their involvement in proliferation, apoptosis, metabolism, and differentiation, they have a key role in the biological processes and pathogenesis of many diseases, including MM. This review summarizes current knowledge of non-coding RNAs (ncRNA), especially lncRNAs, and their role in MM pathogenesis. Undeniable involvement of lncRNAs in MM development suggests their potential as biomarkers.

scholarly journals Extramedullary multiple myeloma patient derived orthotopic xenograft with high disturbed genome: combined exhaustive molecular and therapeutic studies

2021 ◽  
Author(s):  
Lourdes Farre ◽  
Gabriela Sanz ◽  
Neus Ruiz-Xivillé ◽  
Manuel Castro de Moura ◽  
Juan Francisco Martín Tejera ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Testing ◽  
Cutaneous Lesion ◽  
Multiple Myeloma Patient ◽  
Extramedullary Disease ◽  
Orthotopic Xenograft ◽  
Molecular Events ◽  
Epigenetic Events ◽  
Nsg Mouse

Extramedullary multiple myeloma (EMM) has an overall survival of 6 months and occurs in 20% of multiple myeloma (MM) patients. Genetic and epigenetic mechanisms involved in EMM and the therapeutic role of new agents for MM are not well established. Besides, well characterized preclinical models for EMM are not available. Herein, a patient derived orthotopic xenograft (PDOX) was generated from a patient with an aggressive EMM to study in-depth genetic and epigenetic events and drug responses related to extramedullary disease. A fresh punch of an extramedullary cutaneous lesion was orthotopically implanted in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ(NSG) mouse. The PDOX mimicked histologic and phenotypic features of patient's tumor. Cytogenetic studies revealed a hyperploid genome with multiple genetic poor-prognosis alterations. Copy number alterations were detected in all chromosomes. The IGH translocation t(14;16)(q32;q23)IGH/MAF were already observed at medullary stage and a new one, the t(10;14)(p?11-12;q32), were observed only at extramedullary disease and could be eventually related to EMM progression in this case. Exome sequencing showed 24 high impact SNV and 180 indels. From the genes involved, only TP53 was previously described as a driver in MM. A rather balanced proportion of hyper/hypomethylated sites different to previously reported widespread hypomethylation in MM was also observed. Treatment with lenalidomide, dexamethasone and carfilzomib showed a tumor weight reduction of 90% vs. non-treated tumors while the anti-CD38 antibody Daratumumab showed a reduction of 46%. The generation of PDOX from small EMM biopsy allowed to go in-deep to the molecular events associated to extramedullary disease in combination with drug testing.

Primär- und Sekundärprävention des Multiplen Myeloms

2020 ◽  
Vol 145 (12) ◽  
pp. 836-842
Author(s):  
David Cordas dos Santos ◽  
Nicole Erickson ◽  
Lars Gerland ◽  
Franziska Jundt ◽  
Sebastian Theurich
Keyword(s):  
Physical Activity ◽  
Multiple Myeloma ◽  
Life Expectancy ◽  
Current Knowledge ◽  
Lifestyle Factors ◽  
The State ◽  
State Of Health ◽  
Prevention Strategies ◽  
Modifiable Factors

AbstractLifestyle factors such as diet, physical activity and exposure to noxious agents are modifiable factors that have a significant impact on the state of health and life expectancy of humans. The following article is intended to provide an overview of current knowledge on the influence of these lifestyle factors on the development and progression of multiple myeloma and is dedicated to the question of the extent to which prevention strategies can be usefully applied.

scholarly journals A Role for NF-κB in Organ Specific Cancer and Cancer Stem Cells

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 655 ◽  
Author(s):  
Christian Kaltschmidt ◽  
Constanze Banz-Jansen ◽  
Tahar Benhidjeb ◽  
Morris Beshay ◽  
Christine Förster ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Cancer Stem Cells ◽  
Current Knowledge ◽  
Genetic Alterations ◽  
The Status ◽  
Organ Specific ◽  
Proliferation And Metastasis ◽  
Cancer Multiple

Cancer stem cells (CSCs) account for tumor initiation, invasiveness, metastasis, and recurrence in a broad range of human cancers. Although being a key player in cancer development and progression by stimulating proliferation and metastasis and preventing apoptosis, the role of the transcription factor NF-κB in cancer stem cells is still underestimated. In the present review, we will evaluate the role of NF-κB in CSCs of glioblastoma multiforme, ovarian cancer, multiple myeloma, lung cancer, colon cancer, prostate cancer, as well as cancer of the bone. Next to summarizing current knowledge regarding the presence and contribution of CSCs to the respective types of cancer, we will emphasize NF-κB-mediated signaling pathways directly involved in maintaining characteristics of cancer stem cells associated to tumor progression. Here, we will also focus on the status of NF-κB-activity predominantly in CSC populations and the tumor mass. Genetic alterations leading to NF-κB activity in glioblastoma, ependymoma, and multiple myeloma will be discussed.

scholarly journals Targeting EZH2 in Multiple Myeloma—Multifaceted Anti-Tumor Activity

Epigenomes ◽  
2018 ◽  
Vol 2 (3) ◽  
pp. 16 ◽  
Author(s):  
Mohammad Alzrigat ◽  
Helena Jernberg-Wiklund ◽  
Jonathan Licht
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Tumor Suppressor ◽  
Current Knowledge ◽  
Cell Cycle Control ◽  
Cellular Transformation ◽  
Therapeutic Modality ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Adhesion Properties

The enhancer of zeste homolog 2 (EZH2) is the enzymatic subunit of the polycomb repressive complex 2 (PRC2) that exerts important functions during normal development as well as disease. PRC2 through EZH2 tri-methylates histone H3 lysine tail residue 27 (H3K27me3), a modification associated with repression of gene expression programs related to stem cell self-renewal, cell cycle, cell differentiation, and cellular transformation. EZH2 is deregulated and subjected to gain of function or loss of function mutations, and hence functions as an oncogene or tumor suppressor gene in a context-dependent manner. The development of highly selective inhibitors against the histone methyltransferase activity of EZH2 has also contributed to insight into the role of EZH2 and PRC2 in tumorigenesis, and their potential as therapeutic targets in cancer. EZH2 can function as an oncogene in multiple myeloma (MM) by repressing tumor suppressor genes that control apoptosis, cell cycle control and adhesion properties. Taken together these findings have raised the possibility that EZH2 inhibitors could be a useful therapeutic modality in MM alone or in combination with other targeted agents in MM. Therefore, we review the current knowledge on the regulation of EZH2 and its biological impact in MM, the anti-myeloma activity of EZH2 inhibitors and their potential as a targeted therapy in MM.

scholarly journals How I treat smoldering multiple myeloma

Blood ◽  
2014 ◽  
Vol 124 (23) ◽  
pp. 3380-3388 ◽  
Author(s):  
Irene M. Ghobrial ◽  
Ola Landgren
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Clinical Trials ◽  
Plasma Cells ◽  
Current Knowledge ◽  
Bone Marrow Niche ◽  
Course Of Disease ◽  
Smoldering Myeloma ◽  
Patient Enrollment

Abstract Smoldering myeloma is a heterogeneous clinical entity where a subset of patients has an indolent course of disease that mimics monoclonal gammopathy of undermined significance, whereas others have a more aggressive course that has been described as “early myeloma.” It is defined as either serum M-protein ≥3 g/L or ≥10% monoclonal plasma cells in the bone marrow. There are currently no molecular factors to differentiate risks of progression for these patients. Current recommendations of therapy continue to be patient observation or patient enrollment in clinical trials. However, new definitions of active multiple myeloma recently agreed upon by the International Myeloma Working Group may alter the timing of therapy. On the basis of emerging data of therapy in these patients, it seems reasonable to believe that future recommendations for therapy of patients with smoldering myeloma will become an increasingly important topic. In this article, we review the current knowledge of this disease and risk factors associated with progression. We also examine biological insights and alterations that occur in the tumor clone and the surrounding bone marrow niche. Finally, we review clinical trials that have been performed in these patients and provide recommendations for follow-up of patients with this unique disease entity.

scholarly journals Genetic and Epigenetic Events Generate Multiple Pathways in Colorectal Cancer Progression

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Massimo Pancione ◽  
Andrea Remo ◽  
Vittorio Colantuoni
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Current Knowledge ◽  
Alternative Pathway ◽  
Epigenetic Events ◽  
Cells Of Origin ◽  
Common Causes ◽  
Colorectal Cancer Progression

Colorectal cancer (CRC) is one of the most common causes of death, despite decades of research. Initially considered as a disease due to genetic mutations, it is now viewed as a complex malignancy because of the involvement of epigenetic abnormalities. A functional equivalence between genetic and epigenetic mechanisms has been suggested in CRC initiation and progression. A hallmark of CRC is its pathogenetic heterogeneity attained through at least three distinct pathways: a traditional (adenoma-carcinoma sequence), an alternative, and more recently the so-called serrated pathway. While the alternative pathway is more heterogeneous and less characterized, the traditional and serrated pathways appear to be more homogeneous and clearly distinct. One unsolved question in colon cancer biology concerns the cells of origin and from which crypt compartment the different pathways originate. Based on molecular and pathological evidences, we propose that the traditional and serrated pathways originate from different crypt compartments explaining their genetic/epigenetic and clinicopathological differences. In this paper, we will discuss the current knowledge of CRC pathogenesis and, specifically, summarize the role of genetic/epigenetic changes in the origin and progression of the multiple CRC pathways. Elucidation of the link between the molecular and clinico-pathological aspects of CRC would improve our understanding of its etiology and impact both prevention and treatment.

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