Neutrophil Extracellular Traps (NETs) and Hypercoagulability in Plasma Cell Dyscrasias—Is This Phenomenon Worthy of Exploration?

Plasma cell dyscrasias (PCDs) are neoplastic diseases derived from plasma cells. Patients suffering from PCDs are at high risk of hypercoagulability and thrombosis. These conditions are associated with disease-related factors, patient-related factors, or the use of immunomodulatory drugs. As PCDs belong to neoplastic diseases, some other factors related to the cancer-associated hypercoagulability state in the course of PCDs are also considered. One of the weakest issues studied in PCDs is the procoagulant activity of neutrophil extracellular traps (NETs). NETs are web-like structures released from neutrophils in response to different stimuli. These structures are made of deoxyribonucleic acid (DNA) and bactericidal proteins, such as histones, myeloperoxidase, neutrophil elastase, and over 300 other proteins, which are primarily stored in neutrophil granules. NETs immobilize, inactivate the pathogens, and expose them to specialized cells of immune response. Despite their pivotal role in innate immunity, they contribute to the development and exacerbation of autoimmune diseases, trigger inflammatory response, or even facilitate the formation of cancer metastases. NETs were also found to induce activity of coagulation and are considered one of the most important factors inducing thrombosis. Here, we summarize how PCDs influence the release of NETs, and hypothesize whether NETs contribute to hypercoagulability in PCDs patients.

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Plasma cell dyscrasias and normal plasma cells.

Journal of the Japan Society of the Reticuloendothelial System ◽

10.3960/jslrt1961.33.367 ◽

1993 ◽

Vol 33 (6) ◽

pp. 367-376

Author(s):

Hironori Harada ◽

Michio M. Kawano

Keyword(s):

Plasma Cell ◽

Plasma Cells ◽

Normal Plasma ◽

Plasma Cell Dyscrasias

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Cyclooxygenase-2 (COX-2) Is Frequently Expressed in Multiple Myeloma (MM) and Is Associated with Poor Outcome.

Blood ◽

10.1182/blood.v104.11.2450.2450 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2450-2450

Author(s):

Marco Ladetto ◽

Sonia Vallet ◽

Andreas Trojan ◽

Maria Dell’Aquila ◽

Luigia Monitillo ◽

...

Keyword(s):

Flow Cytometry ◽

Plasma Cell ◽

Cell Separation ◽

Plasma Cells ◽

Mrna Level ◽

Prognostic Indicator ◽

Disease Stage ◽

Plasma Cell Dyscrasias ◽

Cox 2 ◽

Ht 29

Abstract Introduction. A perturbed microenvironment with secretion of inflammatory cytokines is typical of MM. Prostaglandins (pg) are implicated in inflammation and angiogenesis and play a role in the pathogenesis of several solid malignancies. Expression of COX-2, the key enzyme of pg synthesis in inflamed tissues, is common in many of these cancers and plays a major role in their development. Moreover, it often acts as a poor prognostic indicator. Despite a large amount of data concerning COX-2 expression in solid tumors, few data are currently available in hematological malignancies. In MM there are several biological, epidemiological and clinical considerations suggesting a potential involvement of the pg pathway. Aim of this study is to verify the involvement of COX-2 in MM and to assess its prognostic role. Patients and methods. COX-2 expression has been assessed by western blotting (WB) as previously described (Du Bois RN, et al, Gastroenterology, 1996). Our positive control was the COX-2 positive cell line HT-29, while bone marrows (BM) from 15 healthy donors were our negative controls. We assessed a panel of 124 samples obtained by 113 patients with plasma cell dyscrasias. Sixteen samples belonged to subjects with MGUS, 80 to patients with MM at diagnosis, and 28 to patients with relapsed/refractory MM. In 11 patients, samples taken at different treatment phases were available. To confirm WB findings and to demonstrate that COX-2 expression occurs in malignant plasma cells immunohistochemistry (IC), and flow cytometry for COX-2 were also performed in 31 and four patients, respectively. Finally, COX-2 expression has been assessed in BM cells from four COX-2 positive patients following selection for the CD138 antigen using the Miltenyi cell separation system. COX-2 expression at the mRNA level has also been assessed by real time quantitative PCR. Results. A dilution test showed that our technique is sensitive enough to detect 2% HT-29 cells in a background of COX-2 negative cells. The 15 normal BM were COX-2 negative. In contrast, COX-2 expression was noticed in 12.5% of MGUS, 34.6% of MM at diagnosis and 56% of MM at relapse. COX-2 positivity at diagnosis and relapse was unrelated to disease stage, BM plasmacytosis, creatinine, Hb levels and ß2 microglobulin. COX-2 expression appeared to be of prognostic relevance: at diagnosis the median time to progression was 14 months in COX-2 positive and 40 months in COX-2 negative subjects (p<0.001). At relapse, of 14 patients showing COX-2 expression, 10 have already died of MM, and four are still alive. In contrast, of 11 COX-2 negative patients only one patient died while 10 are still alive (p<0.001). IC, cell separation and flow cytometry studies indicate that COX-2 expression is related to the malignant plasma cell population. COX-2 mRNA was overexpressed in patients showing increased COX-2 protein expression. Conclusions: a) COX-2 is frequently expressed in plasma cell dyscrasias; b) COX-2 expression is more frequent in advanced disease phases; c) COX-2 expression correlates to a worse outcome. Future studies are required to verify whether COX-2 might be clinically useful as a prognostic marker and/or therapeutic target.

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Inhibition of Interleukin-6 Signaling with CNTO 328 Sensitizes Plasma Cell Dyscrasias to the Effects of Melphalan in Association with Suppression of Signaling through Protein Kinase B/Akt.

Blood ◽

10.1182/blood.v114.22.1836.1836 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1836-1836

Author(s):

Sally A. Hunsucker ◽

Valeria Magarotto ◽

Jairo A. Matthews ◽

Michael Wang ◽

Veerabhadran Baladandayuthapani ◽

...

Keyword(s):

Multiple Myeloma ◽

Protein Kinase ◽

Cell Lines ◽

Plasma Cell ◽

Stromal Cells ◽

Plasma Cells ◽

Protein Kinase B ◽

Myeloma Cell ◽

Ortho Biotech ◽

Plasma Cell Dyscrasias

Abstract Abstract 1836 Poster Board I-862 Background: The neutralizing anti-interleukin (IL)-6 monoclonal antibody (MAb) CNTO 328 acts in an additive to synergistic manner to enhance the activity of bortezomib and dexamethasone against models of multiple myeloma by suppressing several IL-6-induced anti-apoptotic signaling pathways. We therefore sought to evaluate the possibility that blockade of IL-6 signaling could also augment the activity of melphalan, and to determine the potential mechanisms underlying this interaction. Methods: A panel of myeloma cell lines was studied both in suspension and with bone marrow stromal cells to evaluate the activity of CNTO 328 with and without melphalan. The CNTO 328 + melphalan combination was also tested in primary cells from patients with a variety of plasma cell dyscrasias. Results: Treatment of IL-6-dependent KAS-6/1, INA-6, and ANBL-6 myeloma cell lines with CNTO 328 + melphalan reduced plasma cell viability in an additive-to-synergistic manner compared to melphalan with a control MAb. Isobologram analysis demonstrated that the combination was synergistic in KAS-6/1 cells regardless of the sequence of drug treatment (combination indices (CIs) from 0.275-0.607), although the strongest synergy was seen with CNTO 328 pretreatment (CIs from 0.275-0.493). These anti-proliferative effects were accompanied by an enhanced activation of drug-specific apoptosis, and this increased cell death was not rescued by the trophic effects of co-culture of plasma cells with the human-derived stromal cell line HS-5. CNTO 328 increased melphalan-mediated induction of both extrinsic, caspase-8-mediated apoptosis, as well as intrinsic, caspase-9-mediated death, which converged to produce increased levels of caspase-3 activity. Apoptosis was enhanced in part by CNTO 328-stimulated cleavage of Bid to tBid, and alterations in the phosphorylation status of BimEL, as well as increased conversion of Bak and, to a lesser extent, of Bax, to their active forms. Neutralization of IL-6 by CNTO 328 also suppressed signaling through the protein kinase B/Akt pathway, as evidenced by decreased levels of phospho-Akt, and decreased activation of several downstream Akt targets, including p70 S6 kinase and 4E-BP1. Importantly, CNTO 328 + melphalan showed enhanced anti-proliferative effects compared to melphalan and a control MAb against primary CD138+ plasma cells derived from patients with multiple myeloma, monoclonal gammopathy of undetermined significance, and amyloidosis, while demonstrating less toxicity to stromal cells. The enhanced effect of the CNTO 328 + melphalan combination was statistically significant compared to either drug alone (p<0.05) in CD138+ cells isolated from patients who had not received prior melphalan therapy. Conclusions: These studies provide a rationale for translation of CNTO 328 into the clinic in combination with melphalan-based therapies, including either high dose therapy in transplant-eligible patients, or standard dose melphalan-containing induction regimens in transplant-ineligible patients, such as with the combination of bortezomib, melphalan, and prednisone. Disclosures: Voorhees: Millennium Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau. Xie:Centocor Ortho Biotech Inc.: Employment. Cornfeld:Centocor Ortho Biotech Inc.: Employment. Nemeth:Centocor Ortho Biotech Inc.: Employment.

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Combined method of PAP immunocytochemistry and autoradiography: application to cell kinetic study in plasma cell dyscrasias.

Journal of Histochemistry & Cytochemistry ◽

10.1177/35.10.3305704 ◽

1987 ◽

Vol 35 (10) ◽

pp. 1157-1160

Author(s):

T Kanoh ◽

T Ohnaka ◽

H Uchino

Keyword(s):

Plasma Cell ◽

Plasma Cells ◽

Cell Labeling ◽

Combined Method ◽

Cell Kinetic ◽

Diagnosis And Prognosis ◽

Plasma Cell Dyscrasias ◽

Pap Method ◽

Combined Technique

The plasma cell labeling index (LI), in spite of being a reliable indicator for diagnosis and prognosis of multiple myeloma, has been measured in a limited number of laboratories because of technical difficulties. We have developed a new combined technique, using the peroxidase-antiperoxidase (PAP) method and autoradiography, which has several advantages over previously described methods. The primary advantages of our method in the determination of lymphoid-plasma cell LI% are: (a) no damage to slides during storage of more than 1 year; (b) an exact LI measurement in each morphological variety of pleomorphic immunoglobulin-containing cells; (c) no problem in differentiation of lymphoid plasma cells from early red cell precursors; and (d) a separate LI measurement for those lymphoid-plasma cells composed chiefly, if not exclusively, of monoclonal or neoplastic cells. Because of these advantages, this accurate and less difficult technique will facilitate performance of lymphoid plasma cell LI in a number of laboratories.

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Plasma Cell Dyscrasias

Musculoskeletal Imaging Volume 2 ◽

10.1093/med/9780190938178.003.0076 ◽

2019 ◽

pp. 33-38

Author(s):

Kevin B. Hoover

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Clinical Trials ◽

African Americans ◽

Plasma Cell ◽

Plasma Cells ◽

Organ Damage ◽

Disease Staging ◽

Plasma Cell Dyscrasias ◽

Urine Testing

Chapter 76 discusses plasma cell dyscrasias, which are currently incurable diseases resulting from the proliferation of plasma cells and the secretion of immunoglobulins with associated anemia and end-organ damage. These diseases are more common in men than women and more common in African Americans than whites. Multiple myeloma is the most common of the plasma cell dyscrasias. Blood and urine testing, bone marrow biopsy, and radiography are the primary tests used for diagnosis. Radiographs are the standard tools in disease staging and monitoring with advanced imaging used primarily for evaluating symptomatic patients with negative radiographs and patients in clinical trials.

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Myeloma and paraproteinaemias

Oxford Textbook of Medicine ◽

10.1093/med/9780199204854.003.220405_update_002 ◽

2010 ◽

pp. 4342-4355

Author(s):

Robert A. Kyle ◽

S. Vincent Rajkumar

Keyword(s):

Bone Marrow ◽

Renal Insufficiency ◽

Plasma Cell ◽

Plasma Cells ◽

Organ Damage ◽

Bone Lesions ◽

Neoplastic Diseases ◽

End Organ Damage ◽

Single Clone

The paraproteinaemias are a group of neoplastic (or potentially neoplastic) diseases associated with the proliferation of a single clone of immunoglobulin-secreting plasma cells. This asymptomatic condition of unknown cause is characterized by a serum paraprotein concentration under 30 g/l, less than 10% monoclonal plasma cells in the bone marrow, and no evidence of end-organ damage (CRAB) hypercalcaemia, renal insufficiency, anemia, and bone lesions related to the plasma cell proliferative process....

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Gene Expression Profiling of Plasma Cell Dyscrasias: The Role of IGH Translocations in the Heterogeneity of Multiple Myeloma.

Blood ◽

10.1182/blood.v104.11.4845.4845 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4845-4845

Author(s):

Antonino Neri ◽

Michela Mattioli ◽

Luca Agnelli ◽

Sonia Fabris ◽

Luca Baldini ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

Plasma Cell ◽

Plasma Cells ◽

Germ Line ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Plasma Cell Dyscrasia ◽

Transcriptional Level ◽

Plasma Cell Dyscrasias

Abstract Multiple Myeloma (MM) is the most common form of plasma cell dyscrasia, characterized by a marked heterogeneity of genetic lesions and clinical course. It may develop from a premalignant condition (monoclonal gammopathy ofundetermined significance, MGUS) or progress from intra-medullary to extra-medullaryforms (plasma cell leukemia, PCL). To provide insights into the molecular characterization of plasma cell dyscrasias and to investigate the contribution of specific genetic lesions to the biological and clinical heterogeneity of MM, we analyzed the gene expression profiles of plasma cells isolated from 7 MGUS, 39 MM and 6 PCL patients by means of DNA microarrays. MMs resulted highly heterogeneous at transcriptional level, whereas the differential expression of genes mainly involved in DNA metabolism and proliferation distinguished MGUS from PCLs and the majority of MM cases. The clustering of MM patients was mainly driven by the presence of the most recurrent translocations involving the immunoglobulin heavy-chain locus. Distinct signatures have been found to be associated with different lesions: the overexpression of CCND2 and genes involved in cell adhesion pathways was observed in cases with deregulated MAF and MAFB, whereas genes upregulated in cases with the t(4;14) showed apoptosis related functions. In addition, we identified a set of cancer germ-line antigens specifically expressed in a sub-group of MM patients characterized by an aggressive clinical evolution, a finding that could have implications for patient classification and immunotherapy.

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A Comprehensive Biological and Clinical Perspective Can Drive a Patient-Tailored Approach to Multiple Myeloma: Bridging the Gaps between the Plasma Cell and the Neoplastic Niche

Journal of Oncology ◽

10.1155/2020/6820241 ◽

2020 ◽

Vol 2020 ◽

pp. 1-16 ◽

Cited By ~ 2

Author(s):

Antonio Giovanni Solimando ◽

Angelo Vacca ◽

Domenico Ribatti

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Plasma Cells ◽

Scientific Evidence ◽

Therapeutic Window ◽

Extensive Literature ◽

Related Factors ◽

Strategic Approach ◽

Plasma Cell Disorder ◽

Extensive Literature Search

There is a broad spectrum of diseases labeled as multiple myeloma (MM). This is due not only to the composite prognostic risk factors leading to different clinical outcomes and responses to treatments but also to the composite tumor microenvironment that is involved in a vicious cycle with the MM plasma cells. New therapeutic strategies have improved MM patients’ chances of survival. Nevertheless, certain patients’ subgroups have a particularly unfavorable prognosis. Biological stratification can be subdivided into patient, disease, or therapy-related factors. Alternatively, the biological signature of aggressive disease and dismal therapeutic response can promote a dynamic, comprehensive strategic approach, better tailoring the clinical management of high-risk profiles and refractoriness to therapy and taking into account the role played by the MM milieu. By means of an extensive literature search, we have reviewed the state-of-the-art pathophysiological insights obtained from translational investigations of the MM-bone marrow microenvironment. A good knowledge of the MM niche pathophysiological dissection is crucial to tailor personalized approaches in a bench-bedside fashion. The discussion in this review pinpoints two main aspects that appear fundamental in order to gain novel and definitive results from the biology of MM. A systematic knowledge of the plasma cell disorder, along with greater efforts to face the unmet needs present in MM evolution, promises to open a new therapeutic window looking out onto the plethora of scientific evidence about the myeloma and the bystander cells.

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