scholarly journals Identification of biomarkers and signaling pathways during the treatment of multiple myeloma

2021 ◽  
Author(s):  
Hanming Gu
Keyword(s):  
Multiple Myeloma ◽  
Signaling Pathways ◽  
Plasma Cells ◽  
Homo Sapiens ◽  
Hematologic Malignancy ◽  
Protein Processing ◽  
Biological Processes ◽  
Osteolytic Lesions ◽  
Bone Marrow Plasma ◽  
Export Protein

Abstract Multiple myeloma (MM) is an incurable hematologic malignancy, which is characterized by increased bone marrow plasma cells, osteolytic lesions, and anemia. Here, our aim is to characterize significant biomarkers and signaling pathways during the treatment of MM by using bioinformatic methods. The GSE180018 dataset was generated by DNBSEQ-G400 (Homo sapiens). The KEGG and GO analyses showed the biological processes such as " Protein export”, “Protein processing in endoplasmic reticulum”, “Vibrio cholerae infection”, “Fc gamma R-mediated phagocytosis" are mainly affected in FOXM1 KO MM cells. Moreover, we identified the significant genes including CD44, NOTCH1, SELL, RAC2, HSPA8, VAV1, DDIT3, PLK1, HYOU1, ITGAL in FOXM1 KO MM cells. Therefore, our study may provide further guidance for the drug development of MM.

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 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 Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1235
Author(s):  
Tina Paradzik ◽  
Cecilia Bandini ◽  
Elisabetta Mereu ◽  
Maria Labrador ◽  
Elisa Taiana ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Signaling Pathways ◽  
Plasma Cells ◽  
Proteasome Inhibitors ◽  
Treatment Resistance ◽  
Positive Outcome ◽  
Chromatin Remodelers ◽  
Histone Modifiers ◽  
Substantial Progress ◽  
Immune Dysfunctions

Multiple myeloma is a malignancy of terminally differentiated plasma cells, characterized by an extreme genetic heterogeneity that poses great challenges for its successful treatment. Due to antibody overproduction, MM cells depend on the precise regulation of the protein degradation systems. Despite the success of PIs in MM treatment, resistance and adverse toxic effects such as peripheral neuropathy and cardiotoxicity could arise. To this end, the use of rational combinatorial treatments might allow lowering the dose of inhibitors and therefore, minimize their side-effects. Even though the suppression of different cellular pathways in combination with proteasome inhibitors have shown remarkable anti-myeloma activities in preclinical models, many of these promising combinations often failed in clinical trials. Substantial progress has been made by the simultaneous targeting of proteasome and different aspects of MM-associated immune dysfunctions. Moreover, targeting deranged metabolic hubs could represent a new avenue to identify effective therapeutic combinations with PIs. Finally, epigenetic drugs targeting either DNA methylation, histone modifiers/readers, or chromatin remodelers are showing pleiotropic anti-myeloma effects alone and in combination with PIs. We envisage that the positive outcome of patients will probably depend on the availability of more effective drug combinations and treatment of early MM stages. Therefore, the identification of sensitive targets and aberrant signaling pathways is instrumental for the development of new personalized therapies for MM patients.

scholarly journals Multiple myeloma: circulating lymphocytes that express plasma cell antigens

Blood ◽  
1984 ◽  
Vol 64 (2) ◽  
pp. 352-356
Author(s):  
GJ Ruiz-Arguelles ◽  
JA Katzmann ◽  
PR Greipp ◽  
NJ Gonchoroff ◽  
JP Garton ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Peripheral Blood Lymphocytes ◽  
Tumor Burden ◽  
B Cell Differentiation ◽  
Blood Lymphocytes ◽  
Bone Marrow Plasma

The bone marrow and peripheral blood of 14 patients with multiple myeloma were studied with murine monoclonal antibodies that identify antigens on plasma cells (R1–3 and OKT10). Peripheral blood lymphocytes expressing plasma cell antigens were found in six cases. Five of these cases expressed the same antigens that were present on the plasma cells in the bone marrow. Patients that showed such peripheral blood involvement were found to have a larger tumor burden and higher bone marrow plasma cell proliferative activity. In some patients, antigens normally found at earlier stages of B cell differentiation (B1, B2, and J5) were expressed by peripheral blood lymphocytes and/or bone marrow plasma cells.

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 Genome Instability in Multiple Myeloma: Facts and Factors

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5949
Author(s):  
Anna Y. Aksenova ◽  
Anna S. Zhuk ◽  
Artem G. Lada ◽  
Irina V. Zotova ◽  
Elena I. Stepchenkova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Complex Disease ◽  
Plasma Cells ◽  
Genome Instability ◽  
Hematologic Malignancy ◽  
Point Mutations ◽  
Malignant Neoplasm ◽  
Chemotherapeutic Agents ◽  
Hematopoietic Stem ◽  
Social Burden

Multiple myeloma (MM) is a malignant neoplasm of terminally differentiated immunoglobulin-producing B lymphocytes called plasma cells. MM is the second most common hematologic malignancy, and it poses a heavy economic and social burden because it remains incurable and confers a profound disability to patients. Despite current progress in MM treatment, the disease invariably recurs, even after the transplantation of autologous hematopoietic stem cells (ASCT). Biological processes leading to a pathological myeloma clone and the mechanisms of further evolution of the disease are far from complete understanding. Genetically, MM is a complex disease that demonstrates a high level of heterogeneity. Myeloma genomes carry numerous genetic changes, including structural genome variations and chromosomal gains and losses, and these changes occur in combinations with point mutations affecting various cellular pathways, including genome maintenance. MM genome instability in its extreme is manifested in mutation kataegis and complex genomic rearrangements: chromothripsis, templated insertions, and chromoplexy. Chemotherapeutic agents used to treat MM add another level of complexity because many of them exacerbate genome instability. Genome abnormalities are driver events and deciphering their mechanisms will help understand the causes of MM and play a pivotal role in developing new therapies.

scholarly journals Che-1/AATF-induced transcriptionally active chromatin promotes cell proliferation in multiple myeloma

2020 ◽  
Vol 4 (22) ◽  
pp. 5616-5630
Author(s):  
Tiziana Bruno ◽  
Francesca De Nicola ◽  
Giacomo Corleone ◽  
Valeria Catena ◽  
Frauke Goeman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Rna Polymerase Ii ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Global Gene Expression ◽  
Clonal Expansion ◽  
Genetic Alterations ◽  
Active Chromatin ◽  
Promising Target ◽  
External Domain

Abstract Multiple myeloma (MM) is a hematologic malignancy produced by a clonal expansion of plasma cells and characterized by abnormal production and secretion of monoclonal antibodies. This pathology exhibits an enormous heterogeneity resulting not only from genetic alterations but also from several epigenetic dysregulations. Here we provide evidence that Che-1/AATF (Che-1), an interactor of RNA polymerase II, promotes MM proliferation by affecting chromatin structure and sustaining global gene expression. We found that Che-1 depletion leads to a reduction of “active chromatin” by inducing a global decrease of histone acetylation. In this context, Che-1 directly interacts with histones and displaces histone deacetylase class I members from them. Strikingly, transgenic mice expressing human Che-1 in plasma cells develop MM with clinical features resembling those observed in the human disease. Finally, Che-1 downregulation decreases BRD4 chromatin accumulation to further sensitize MM cells to bromodomain and external domain inhibitors. These findings identify Che-1 as a promising target for MM therapy, alone or in combination with bromodomain and external domain inhibitors.

Tooth Extraction Locally Stimulates Proliferation of Multiple Myeloma in a Patient with Mandibular Localizations

2017 ◽  
Vol 138 (4) ◽  
pp. 201-207 ◽  
Author(s):  
Jean-Daniel Kün-Darbois ◽  
Léonie Quenel ◽  
Smaïl Badja ◽  
Daniel Chappard
Keyword(s):  
Multiple Myeloma ◽  
Tooth Extraction ◽  
Soft Tissues ◽  
Plasma Cells ◽  
Osteonecrosis Of The Jaw ◽  
Surgical Trauma ◽  
Osteolytic Lesions ◽  
X Ray ◽  
Extraction Site ◽  
The Right

Objectives: Multiple myeloma (MM) is characterized by the occurrence of osteolytic lesions. MM treatment usually involves antiresorptive drugs (mainly bisphosphonates). Case Report: A patient with an MM presented osteolytic lesions of the mandible. Extraction of teeth 45 and 46 was performed 5 years after the diagnosis of periodontitis. Four months later, osteonecrosis of the jaw (ONJ) was diagnosed at the extraction site. X-ray showed an extension of osteolytic lesions on the right side, close to the extraction site, without modification of the lesions on the left side. Two months later, a curettage was performed because of a painful bone sequestration. X-ray showed an extension of the osteolytic lesions on the right side. Results: Histological analysis found a vascularized plasmacytoma of the soft tissues around the ONJ. Analysis of the bone showed mixed lesions with osteonecrotic areas and living bone resorbed by active osteoclasts surrounding a plasmacytoma. The surface area of the osteolytic foci has considerably increased only close to the extraction site. Conclusions: Tooth extraction triggered an ONJ associated with bisphosphonate treatment. However, it also seemed to induce a considerable proliferation of plasma cells at the extraction site; we hypothesize that it is due to the increase in bone remodeling related to the surgical trauma.

scholarly journals Functional Comparison between Healthy and Multiple Myeloma Adipose Stromal Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Nicolas Espagnolle ◽  
Benjamin Hebraud ◽  
Jean-Gérard Descamps ◽  
Mélanie Gadelorge ◽  
Marie-Véronique Joubert ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stromal Cells ◽  
Cellular Therapy ◽  
Plasma Cells ◽  
Bone Lesions ◽  
Adipose Stromal Cells ◽  
Osteolytic Lesions ◽  
Healthy Donors ◽  
Bone Damage ◽  
First Time

Multiple myeloma (MM) is an incurable B cell neoplasia characterized by the accumulation of tumor plasma cells within the bone marrow (BM). As a consequence, bone osteolytic lesions develop in 80% of patients and remain even after complete disease remission. We and others had demonstrated that BM-derived mesenchymal stromal cells (MSCs) are abnormal in MM and thus cannot be used for autologous treatment to repair bone damage. Adipose stromal cells (ASCs) represent an interesting alternative to MSCs for cellular therapy. Thus, in this study, we wondered whether they could be a good candidate in repairing MM bone lesions. For the first time, we present a transcriptomic, phenotypic, and functional comparison of ASCs from MM patients and healthy donors (HDs) relying on their autologous MSC counterparts. In contrast to MM MSCs, MM ASCs did not exhibit major abnormalities. However, the changes observed in MM ASCs and the supportive property of ASCs on MM cells question their putative and safety uses at an autologous or allogenic level.

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