scholarly journals A Cancer-Related microRNA Signature Shows Biomarker Utility in Multiple Myeloma

2021 ◽  
Vol 22 (23) ◽  
pp. 13144
Author(s):  
Aristea-Maria Papanota ◽  
Paraskevi Karousi ◽  
Christos K. Kontos ◽  
Pinelopi I. Artemaki ◽  
Christine-Ivy Liacos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Regulation Of Gene Expression ◽  
In Silico Analysis ◽  
Bone Lesions ◽  
Real Time Quantitative Pcr ◽  
Skeletal Related Events ◽  
Adapter Primer ◽  
Post Transcriptional Regulation

Multiple myeloma (MM) is the second most common hematological malignancy, arising from terminally differentiated B cells, namely plasma cells. miRNAs are small non-coding RNAs that participate in the post-transcriptional regulation of gene expression. In this study, we investigated the role of nine miRNAs in MM. CD138+ plasma cells were selected from bone marrow aspirates from MM and smoldering MM (sMM) patients. Total RNA was extracted and in vitro polyadenylated. Next, first-strand cDNA synthesis was performed using an oligo-dT–adapter primer. For the relative quantification of the investigated miRNAs, an in-house real-time quantitative PCR (qPCR) assay was developed. A functional in silico analysis of the miRNAs was also performed. miR-16-5p and miR-155-5p expression was significantly lower in the CD138+ plasma cells of MM patients than in those of sMM patients. Furthermore, lower levels of miR-15a-5p, miR-16-5p, and miR-222-3p were observed in the CD138+ plasma cells of MM patients with osteolytic bone lesions, compared to those without. miR-125b-5p was also overexpressed in the CD138+ plasma cells of MM patients with bone disease that presented with skeletal-related events (SREs). Furthermore, lower levels of miR-223-3p were associated with significantly worse overall survival in MM patients. In conclusion, we propose a miRNA signature with putative clinical utility in MM.

scholarly journals tRNA Derivatives in Multiple Myeloma: Investigation of the Potential Value of a tRNA-Derived Molecular Signature

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1811
Author(s):  
Paraskevi Karousi ◽  
Aristea-Maria Papanota ◽  
Pinelopi I. Artemaki ◽  
Christine-Ivy Liacos ◽  
Dimitrios Patseas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
In Silico Analysis ◽  
Staging System ◽  
Molecular Signature ◽  
Real Time Quantitative Pcr ◽  
Favorable Prognosis ◽  
Clonal Proliferation

Multiple myeloma (MM) is a hematologic malignancy arising from the clonal proliferation of malignant plasma cells. tRNA-derived RNA fragments (tRFs) constitute a class of small non-coding RNAs, deriving from specific enzymatic cleavage of tRNAs. To the best of our knowledge, this is one of few studies to uncover the potential clinical significance of tRFs in MM. Total RNA was extracted from CD138+ plasma cells of MM and smoldering MM patients, and in vitro polyadenylated. First-strand cDNA synthesis was performed, priming from an oligo-dT-adaptor sequence. Next, real-time quantitative PCR (qPCR) assays were developed for the quantification of six tRFs. Biostatistical analysis was performed to assess the results and in silico analysis was conducted to predict the function of one of the tRFs. Our results showed that elevated levels of five out of six tRFs are indicators of favorable prognosis in MM, predicting prolonged overall survival (OS), while two of them constitute potential molecular biomarkers of favorable prognosis in terms of disease progression. Moreover, three tRFs could be used as surrogate prognostic biomarkers along with the R-ISS staging system to predict OS. In conclusion, tRFs show molecular biomarker utility in MM, while their mechanisms of function merit further investigation.

Bone disease as the first manifestation of systemic AL-amyloidosis

2020 ◽  
Vol 92 (7) ◽  
pp. 85-89
Author(s):  
L. P. Mendeleeva ◽  
I. G. Rekhtina ◽  
A. M. Kovrigina ◽  
I. E. Kostina ◽  
V. A. Khyshova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Disease ◽  
Plasma Cells ◽  
Interventricular Septum ◽  
Bone Destruction ◽  
Amyloid Deposition ◽  
Bone Lesions ◽  
Al Amyloidosis ◽  
Linear Type

Our case demonstrates severe bone disease in primary AL-amyloidosis without concomitant multiple myeloma. A 30-year-old man had spontaneous vertebral fracture Th8. A computed tomography scan suggested multiple foci of lesions in all the bones. In bone marrow and resected rib werent detected any tumor cells. After 15 years from the beginning of the disease, nephrotic syndrome developed. Based on the kidney biopsy, AL-amyloidosis was confirmed. Amyloid was also detected in the bowel and bone marrow. On the indirect signs (thickening of the interventricular septum 16 mm and increased NT-proBNP 2200 pg/ml), a cardial involvement was confirmed. In the bone marrow (from three sites) was found 2.85% clonal plasma cells with immunophenotype СD138+, СD38dim, СD19-, СD117+, СD81-, СD27-, СD56-. FISH method revealed polysomy 5,9,15 in 3% of the nuclei. Serum free light chain Kappa 575 mg/l (/44.9) was detected. Multiple foci of destruction with increased metabolic activity (SUVmax 3.6) were visualized on PET-CT, and an surgical intervention biopsy was performed from two foci. The number of plasma cells from the destruction foci was 2.5%, and massive amyloid deposition was detected. On CT scan foci of lesions differed from bone lesions at multiple myeloma. Bone fragments of point and linear type (button sequestration) were visualized in most of the destruction foci. The content of the lesion was low density. There was no extraossal spread from large zones of destruction. There was also spontaneous scarring of the some lesions (without therapy). Thus, the diagnosis of multiple myeloma was excluded on the basis based on x-ray signs, of the duration of osteodestructive syndrome (15 years), the absence of plasma infiltration in the bone marrow, including from foci of bone destruction by open biopsy. This observation proves the possibility of damage to the skeleton due to amyloid deposition and justifies the need to include AL-amyloidosis in the spectrum of differential diagnosis of diseases that occur with osteodestructive syndrome.

scholarly journals Bioactive Compounds from Herbal Medicine Targeting Multiple Myeloma

2021 ◽  
Vol 11 (10) ◽  
pp. 4451
Author(s):  
Coralia Cotoraci ◽  
Alina Ciceu ◽  
Alciona Sasu ◽  
Eftimie Miutescu ◽  
Anca Hermenean
Keyword(s):  
Multiple Myeloma ◽  
Survival Rate ◽  
Plasma Cells ◽  
Inhibition Of Proliferation ◽  
In Vivo Experiments ◽  
Clonal Proliferation ◽  
Hematological Cancers ◽  
Monoclonal Proteins

Multiple myeloma (MM) is one of the most widespread hematological cancers. It is characterized by a clonal proliferation of malignant plasma cells in the bone marrow and by the overproduction of monoclonal proteins. In recent years, the survival rate of patients with multiple myeloma has increased significantly due to the use of transplanted stem cells and of the new therapeutic agents that have significantly increased the survival rate, but it still cannot be completely cured and therefore the development of new therapeutic products is needed. Moreover, many patients have various side effects and face the development of drug resistance to current therapies. The purpose of this review is to highlight the bioactive active compounds (flavonoids) and herbal extracts which target dysregulated signaling pathway in MM, assessed by in vitro and in vivo experiments or clinical studies, in order to explore their healing potential targeting multiple myeloma. Mechanistically, they demonstrated the ability to promote cell cycle blockage and apoptosis or autophagy in cancer cells, as well as inhibition of proliferation/migration/tumor progression, inhibition of angiogenesis in the tumor vascular network. Current research provides valuable new information about the ability of flavonoids to enhance the apoptotic effects of antineoplastic drugs, thus providing viable therapeutic options based on combining conventional and non-conventional therapies in MM therapeutic protocols.

scholarly journals Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma

Oncogene ◽  
2021 ◽  
Author(s):  
Yinyin Xu ◽  
Jing Guo ◽  
Jing Liu ◽  
Ying Xie ◽  
Xin Li ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combined Treatment ◽  
Hypoxia Inducible Factor ◽  
Bone Destruction ◽  
Bone Lesions ◽  
Myeloma Cells ◽  
Downstream Target ◽  
Dkk1 Expression

AbstractMyeloma cells produce excessive levels of dickkopf-1 (DKK1), which mediates the inhibition of Wnt signaling in osteoblasts, leading to multiple myeloma (MM) bone disease. Nevertheless, the precise mechanisms underlying DKK1 overexpression in myeloma remain incompletely understood. Herein, we provide evidence that hypoxia promotes DKK1 expression in myeloma cells. Under hypoxic conditions, p38 kinase phosphorylated cAMP-responsive element-binding protein (CREB) and drove its nuclear import to activate DKK1 transcription. In addition, high levels of DKK1 were associated with the presence of focal bone lesions in patients with t(4;14) MM, overexpressing the histone methyltransferase MMSET, which was identified as a downstream target gene of hypoxia-inducible factor (HIF)-1α. Furthermore, we found that CREB could recruit MMSET, leading to the stabilization of HIF-1α protein and the increased dimethylation of histone H3 at lysine 36 on the DKK1 promoter. Knockdown of CREB in myeloma cells alleviated the suppression of osteoblastogenesis by myeloma-secreted DKK1 in vitro. Combined treatment with a CREB inhibitor and the hypoxia-activated prodrug TH-302 (evofosfamide) significantly reduced MM-induced bone destruction in vivo. Taken together, our findings reveal that hypoxia and a cytogenetic abnormality regulate DKK1 expression in myeloma cells, and provide an additional rationale for the development of therapeutic strategies that interrupt DKK1 to cure MM.

scholarly journals The oxidative stress response regulates DKK1 expression through the JNK signaling cascade in multiple myeloma plasma cells

Blood ◽  
2007 ◽  
Vol 109 (10) ◽  
pp. 4470-4477 ◽  
Author(s):  
Simona Colla ◽  
Fenghuang Zhan ◽  
Wei Xiong ◽  
Xiaosong Wu ◽  
Hongwei Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Multiple Myeloma ◽  
Wnt Signaling ◽  
Plasma Cells ◽  
Cell Types ◽  
Signaling Cascade ◽  
Jnk Pathway ◽  
Jnk Signaling ◽  
Dkk1 Expression

Abstract Multiple myeloma (MM) plasma cells, but not those from healthy donors and patients with monoclonal gammopathy of undetermined significance or other plasma cell dyscrasias involving the bone marrow, express the Wnt-signaling antagonist DKK1. We previously reported that secretion of DKK1 by MM cells likely contributes to osteolytic lesions in this disease by inhibiting Wnt signaling, which is essential for osteoblast differentiation and survival. The mechanisms responsible for activation and regulation of DKK1 expression in MM are not known. Herein, we could trace DKK1 expression changes in MM cells to perturbations in the JNK signaling cascade, which is differentially modulated through oxidative stress and interactions between MM cells with osteoclasts in vitro. Despite its role as a tumor suppressor and mediator of apoptosis in other cell types including osteoblasts, our data suggest that DKK1, a stress-responsive gene in MM, does not mediate apoptotic signaling, is not activated by TP53, and its forced overexpression could not inhibit cell growth or sensitize MM cells to apoptosis following treatment with thalidomide or lenalidomide. We conclude that specific strategies to modulate persistent activation of the JNK pathway may be beneficial in preventing disease progression and treating myeloma-associated bone disease by inhibiting DKK1 expression.

scholarly journals Differential Expression of MicroRNA-19b Promotes Proliferation of Cancer Stem Cells by Regulating the TSC1/mTOR Signaling Pathway in Multiple Myeloma

2018 ◽  
Vol 50 (5) ◽  
pp. 1804-1814 ◽  
Author(s):  
Ni Wang ◽  
Xiaohua Liang ◽  
Weijian Yu ◽  
Shihang Zhou ◽  
Meiyun  Fang
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Cancer Stem Cells ◽  
Real Time ◽  
Caspase 3 ◽  
In Silico Analysis ◽  
Luciferase Assay ◽  
Downstream Target ◽  
Induced Apoptosis

Background/Aims: MiR-19b has been reported to be involved in several malignancies, but its role in multiple myeloma (MM) is still unknown. The objective of this study was to explore the biological mechanism of miR-19b in the progression of MM. Methods: First, we performed real-time polymerase chain reaction (PCR) and Western blot to study the expression of miR-19b, tuberous sclerosis 1 (TSC1), and caspase-3 in different groups. MTT assay was performed to explore the effect of miR-19b on survival and apoptosis of cancer stem cells (CSCs). Computation analysis and luciferase assay were utilized to confirm the interaction between miR-19b and TSC1. Results: A total of 38 participants comprising 20 subjects with MM and 18 healthy subjects as normal controls were enrolled in our study. Real-time PCR showed dramatic upregulation of miR-19b, but TSC1 was evidently suppressed in the MM group. MiR-19b overexpression substantially promoted clonogenicity and cell viability, and further inhibited apoptosis of CSCs in vitro. Furthermore, miR-19b overexpression downregulated the expression of caspase-3, which induced apoptosis. Using in silico analysis, we identified that TSC1 might be a direct downstream target of miR-19b, and this was further confirmed by luciferase assay showing that miR-19b apparently reduced the luciferase activity of wild-type TSC1 3´-UTR, but not that of mutant TSC1 3´-UTR. There was also evident decrease in TSC1 mRNA and protein in CSCs following introduction of miR-19b. Interestingly, reintroduction of TSC1 abolished the miR-19b-induced proliferation promotion and apoptosis inhibition in CSCs. Conclusion: These findings collectively suggest that miR-19b promotes cell survival and suppresses apoptosis of MM CSCs via targeting TSC1 directly, indicating that miR-19b may serve as a potential and novel therapeutic target of MM based on miRNA expression.

scholarly journals An Unprecedented Case of p190 BCR-ABL Chronic Myeloid Leukemia Diagnosed during Treatment for Multiple Myeloma: A Case Report and Review of the Literature

2018 ◽  
Vol 2018 ◽  
pp. 1-5
Author(s):  
Kosuke Miki ◽  
Naoshi Obara ◽  
Kenichi Makishima ◽  
Tatsuhiro Sakamoto ◽  
Manabu Kusakabe ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Plasma Cells ◽  
Bone Marrow Examination ◽  
Bone Lesions ◽  
Dexamethasone Treatment ◽  
Lytic Bone Lesions

We report the case of a 76-year-old man who was diagnosed as having chronic myeloid leukemia (CML) with p190 BCR-ABL while receiving treatment for symptomatic multiple myeloma (MM). The diagnosis of MM was based on the presence of serum M-protein, abnormal plasma cells in the bone marrow, and lytic bone lesions. The patient achieved a partial response to lenalidomide and dexamethasone treatment. However, 2 years after the diagnosis of MM, the patient developed leukocytosis with granulocytosis, anemia, and thrombocytopenia. Bone marrow examination revealed Philadelphia chromosomes and chimeric p190 BCR-ABL mRNA. Fluorescence in situ hybridization also revealed BCR-ABL-positive neutrophils in the peripheral blood, which suggested the emergence of CML with p190 BCR-ABL. The codevelopment of MM and CML is very rare, and this is the first report describing p190 BCR-ABL-type CML coexisting with MM. Moreover, we have reviewed the literature regarding the coexistence of these diseases.

scholarly journals IL-32 is a metabolic regulator promoting survival and proliferation of malignant plasma cells

2021 ◽  
Author(s):  
Kristin Roseth Aass ◽  
Robin Mjelle ◽  
Martin H. Kastnes ◽  
Synne S. Tryggestad ◽  
Luca M. van den Brink ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Oxidative Phosphorylation ◽  
Plasma Cells ◽  
Inflammatory Diseases ◽  
Mitochondrial Respiratory Chain ◽  
Gene Signature ◽  
Growth And Survival ◽  
Novel Concept

AbstractIL-32 is a non-classical cytokine expressed in cancers, inflammatory diseases and infections. IL-32 can have both extracellular and intracellular functions, and its receptor is not identified. We here demonstrate that endogenously expressed, intracellular IL-32 binds to components of the mitochondrial respiratory chain and promotes oxidative phosphorylation. Knocking out IL-32 in malignant plasma cells significantly reduced survival and proliferation in vitro and in vivo. High throughput transcriptomic and MS-metabolomic profiling of IL-32 KO cells revealed that loss of IL-32 leads to profound perturbations in metabolic pathways, with accumulation of lipids, pyruvate precursors and citrate, indicative of reduced mitochondrial function. IL-32 is expressed in a subgroup of multiple myeloma patients with an inferior prognosis. Primary myeloma cells expressing IL-32 were characterized by a plasma cell gene signature associated with immune activation, proliferation and oxidative phosphorylation. We propose a novel concept for regulation of metabolism by an intracellular cytokine and identify IL-32 as an endogenous growth and survival factor for malignant plasma cells. IL-32 is a potential prognostic biomarker and a treatment target in multiple myeloma.

scholarly journals The Evolution in The Treatment of Multiple Myeloma Towards Targeted Magnetic Molecularly Imprinted Nanomedicines

2015 ◽  
pp. 1-2
Author(s):  
Edgar Pérez-Herrero
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bacterial Infections ◽  
Plasma Cells ◽  
The Body ◽  
Western World ◽  
Bone Lesions ◽  
Non Hodgkin Lymphoma ◽  
Clonal Proliferation ◽  
Tract Infections

Multiple myeloma is the second more frequently haematological cancer in the western world, after non-Hodgkin lymphoma, being about the 1-2 % of all the cancers cases and the 10-13% of hematologic diseases. The disease is caused by an uncontrolled clonal proliferation of plasma cells in the bone marrow that accumulate in different parts of the body, usually in the bone marrow, around some bones, and rarely in other tissues, forming tumor deposits, called plasmocytomas. This uncontrolled clonal proliferation of plasma cells produces the secretion of an abnormal monoclonal immunoglobulin (paraprotein or M-protein) and prevents the formation of the other antibodies produced by the normal plasma cells that are destroyed. The anormal secretion of paraproteins unbalance the osteoblastosis and osteoclastosis processes, leading to bone lesions that cause lytic bone deposits and the release of calcium from bones (hypercalcemia) that may produce renal failure. Regions affected by bone lesions are the skull, spine, ribs, sternum, pelvis and bones that form part of the shoulders and hips. The substitution of the healthy bone marrow by infiltrating malignant cells and the inhibition of the normal production of red blood cells produce anaemia, thrombocytopenia and leukopenia. Multiple myeloma patients are immunosuppressed because of leukopenia and the abnormal immunoglobulin production caused by the uncontrolled clonal proliferation of plasma cells, being susceptible to bacterial infections, like pneumonias and urinary tract infections. The interaction of immunoglobulin with hemostatic mechanisms may lead to haemorrhagic diathesis or thrombosis. Also, disorders of the central and peripheral nervous system are part of the disease, being the more common neurological manifestations the spinal cord compressions and the peripheral neuropathies.

scholarly journals Production of interleukin-1 by bone marrow myeloma cells

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 380-387 ◽  
Author(s):  
F Cozzolino ◽  
M Torcia ◽  
D Aldinucci ◽  
A Rubartelli ◽  
A Miliani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Interleukin 1 ◽  
Long Bone ◽  
Bone Lesions ◽  
Normal Donor ◽  
Biologic Activity ◽  
Culture Supernatants

Plasma cells isolated from bone marrow (BM) aspirates of 12 patients with multiple myeloma (MM) and nine patients with monoclonal gammopathy of undetermined significance (MGUS) were analyzed for production of cytokines with bone-resorbing activity, such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and lymphotoxin (LT). Culture supernatants of plasma cells from MM, but not from MGUS or normal donor, invariably contained high amounts of IL-1-beta and lower amounts of IL-1-alpha. With a single exception, TNF/LT biologic activity was not detected in the same supernatants. IL-6 was present in two of five supernatants tested. Normal B lymphocytes released both IL-1 and TNF/LT activities for four days after activation in vitro; however, production of these cytokines ceased at the final stage of plasma cell. Unexpectedly, the mRNA extracted from MM plasma cell hybridized with TNF- and LT- specific, as well as IL-1-specific probes, although the culture supernatants did not contain detectable TNF/LT biologic activity. When tested in the fetal rat long bone assay, MM plasma cell supernatants displayed a strong osteoclast-activating factor (OAF) activity, which was greatly reduced but not completely abolished by neutralizing anti- IL-1 antibodies. Anti-TNF or anti-LT antibodies were ineffective in the same test. We conclude that the IL-1 released in vivo by malignant plasma cells has a major role in pathogenesis of lytic bone lesions of human MM.

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