scholarly journals Inositol Polyphosphate 4-Phosphatase Type II Is a Tumor Suppressor in Multiple Myeloma

2022 ◽  
Vol 11 ◽  
Author(s):  
Yafei Wang ◽  
Lin Chen ◽  
Qian Li ◽  
Shuang Gao ◽  
Su Liu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tumor Suppressor ◽  
Plasma Cells ◽  
Mammalian Target Of Rapamycin ◽  
Inhibitory Effect ◽  
Extramedullary Plasmacytoma ◽  
Type Ii ◽  
Inositol Polyphosphate ◽  
Loss Of Function ◽  
Normal Plasma

Inositol polyphosphate-4-phosphatase type II (INPP4B) has been identified as a tumor suppressor, while little is known about its expression and function in multiple myeloma (MM). In this study, we evaluated the expression of INPP4B in 28 cases of newly diagnosed MM patients and 42 cases of extramedullary plasmacytoma (EMP) patients compared with normal plasma cells and found that low INPP4B expression was correlated with poor outcomes in MM patients. Moreover, expression of INPP4B in seven MM cell lines was all lower than that in normal plasma cells. In addition, loss of function of INPP4B promoted cell proliferation in MM cells; however, gain of function suppressed MM cells proliferation and arrested the cell cycle at G0/G1 phage. Meanwhile, knockdown of INPP4B enhanced resistance, but overexpression promoted sensitivity to bortezomib treatment in MM cells. Mechanistically, we found that INPP4B exerted its role via inhibiting the phosphorylation of Akt at lysine 473 but not threonine 308, which attenuated the activation of the PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway. Therefore, we identified an inhibitory effect of INPP4B in MM, and our findings suggested that loss of INPP4B expression is a risk factor of aggressive MM.

scholarly journals Pulsatile Midline Solitary Plasmacytoma in the Frontal Head Region-A Case Report”

2016 ◽  
Vol 32 (1) ◽  
pp. 39-42
Author(s):  
Md Atikur Rahman ◽  
Aklaque Hossain Khan ◽  
Kanak Kanti Barua
Keyword(s):  
Multiple Myeloma ◽  
Differential Diagnosis ◽  
Case Report ◽  
Histological Examination ◽  
Plasma Cells ◽  
Extramedullary Plasmacytoma ◽  
Solitary Plasmacytoma ◽  
Rare Entity ◽  
Head Region ◽  
Malignant Plasma Cell

Primary craniocerebral plasmacytomas are uncommon and represent only 0.7 % of all plasmacytomas. In this case solitary plasmacytoma in the midline frontal head region of the skull and discuss the clinical features and prognosis of this tumor. Plasmacytoma can present as multiple myeloma, solitary plasmacytoma of the bone or extramedullary plasmacytoma. Solitary plasmacytoma is a rare entity that composes of malignant plasma cells and involves the bone to form only one or two lesions without evidence of disease dissemination. It accounts for only 4% of malignant plasma cell tumors. 50 years old male was suffering from plasmacytoma in the frontal head region in our case which is pulsatile. On images showed multiple differential diagnosis but after operation histological examination revealed plasmacytoma. Bangladesh Journal of Neuroscience 2016; Vol. 32 (1): 39-42

scholarly journals PC3 - 216 Presentation of Intradural Extramedullary Plasmacytoma with Intratumoral Hemorrhage: Case Report and Review of Literature

2016 ◽  
Vol 43 (S4) ◽  
pp. S22-S22
Author(s):  
A. Ghare ◽  
F. Haji ◽  
K. MacDougall
Keyword(s):  
Multiple Myeloma ◽  
Differential Diagnosis ◽  
Plasma Cells ◽  
Extramedullary Plasmacytoma ◽  
Left Frontal Lobe ◽  
Axial Mass ◽  
Dural Tail ◽  
History Of ◽  
Intradural Extramedullary ◽  
Contrast Ct

Plasmacytomas are solitary tumours characterized by neoplastic proliferation of plasma cells and can be found isolated or in associated with multiple myeloma. Plasmacytomas uncommonly occur intracranially, and dural plasmacytomas without involvement of the calvarium are exceedingly rare. Reported cases indicate durally-based plasmacytomas mimick the appearance of meningioma, lymphoma or sarcoma of the dura. The authors report a case of a 77-year-old male with known multiple myeloma who presented with a 3-week history of confusion, speech impediment, and right sided weakness. A non-contrast CT scan revealed a dense extra-axial mass in the left frontal lobe with initial concerns of an extra-axial hemorrhage. A subsequent MRI demonstrated a contrast enhancing mass with a broad-based dural tail and no underlying calvarial lesion. Differential diagnosis included meningioma or intracranial plasmacytoma. The patient underwent surgical resection and was found to have intratumoural hemorrhage, with pathology confirming plasmacytoma. In the published literature, there are only 20 prior reports of dural plasmacytomas (with and without primary calvarial infiltration), of which only five previous cases reported associated intratumoural hemorrhage. Our case, along with this literature, suggests that new onset of focal neurologic deficits in patients with a history of multiple myeloma merits careful investigation, and that intracranial plasmacytoma should be considered on the differential diagnosis even when imaging reveals masses consistent with hemorrhage or meningioma.

Microrna Expression Profile Identifies Distinct Clinically Relevant Sub-Groups in Multiple Myeloma: Novel Prognostic Markers and Potential Targets for Therapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 96-96 ◽  
Author(s):  
Sophia Adamia ◽  
Herve AvetLoiseau ◽  
Samirkumar B Amin ◽  
Yu-Tzu Tai ◽  
Steven P. Treon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Differentiation ◽  
Clinical Outcome ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Plasma Cells ◽  
Normal Plasma ◽  
Group A ◽  
Group B

Abstract MicroRNA, an abundant class of small endogenous RNAs, regulate target genes through inducing translational inhibition and cleavage of targeted transcripts. To date, microRNAs have been implicated in normal biological processes, including development, cell differentiation, apoptosis and proliferation as well as in malignant transformation. However, their role in multiple myeloma (MM) remains unknown. Here we investigated role of microRNAs in myelomagenesis, and their influence on prognosis and clinical outcome. We evaluated profiles of 384 microRNAs in bone marrow derived CD138+ plasma cells (PC) from 79 uniformly treated MM patients, 11 MM cell lines and 9 healthy donors using qRT-PCR based microRNA array. The relative expression was calculated using comparative Ct method, and data was normalized using endogenous controls and analyzed using SDS, RQ manager, R and dChip softwares. MicroRNA expression profiles detected in MM patients were correlated with clinical outcome measures. We observed significant modulate expression of 61 microRNAs in myeloma cells compared to normal plasma cells. When more stringent criteria were used, we identified 24 differentially expressed microRNAs in patient samples. Further, unsupervised hierarchical clustering of filtered microRNAs, based on their DCt values, identified two major groups within the MM population (groups A and group B). Samples of Group A clusters with MM cell lines, indicating more proliferative nature of MM patient cells. Within B group, a second degree node group B2, clusters with normal plasma cells indicating more indolent course, while patients in an additional node B1 represented an assorted pattern. The unsupervised clustering of all MM samples showed consistent changes in miR-30b, -30c, -30d, -142-5p, -24, -191, -181d, -374, -146b, -140, -145, -125a, -151, -223, -155, let7b, indicative of a role of these microRNA in myelomagenesis; while supervised analysis of samples within groups A and B identified modulated expression of different sets of miRNAs. In group A miR-585 and let-7f were upregulated 8–12 fold, while miRs -125a, -126, -155, -223, -146a, -374 -19a, -20a, -26a, -30a -5p, -30b, and -30d were significantly downregulated; in group B, all differentially expressed microRNAs were downregulated (p<0.001) compared to normal plasma cells. These modulated miRNAs target critical signaling pathways including apoptosis, hematopoietic cell differentiation and proliferation, survival and angiogenesis by upregulating function of HOX9, c-myc, VCAM-1, Bcl-2, E2F1, SHP1, SHP2, VEGF, and DUSp6 molecules. We further analyzed the effect of microRNA on clinical outcome. We have observed significantly superior event free and overall survival of patients in group B2 compared to patients in group A (2 yr estimated EFS 79% versus 54% respectively; p=0.05; and 2 yr estimated OS 94% versus 70% respectively; p =0.017). Taken together this data identifies critical microRNAs as modulators of gene expression and signaling pathways and provides potential novel microRNA and gene targets in MM to both understand biological behavior and for therapeutic application.

A Potential Biomarker Panel of Multiple Myeloma Identified Using Label-Free Mass Spectrometry-Based Quantitative Proteomics

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2890-2890
Author(s):  
Attaya Suvannasankha ◽  
Colin D. Crean ◽  
Heather M. Sahm ◽  
Rafat Abonour ◽  
Sherif Farag ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Multiple Myeloma ◽  
Protein Expression ◽  
Plasma Cells ◽  
Expression Profiles ◽  
Peptide Identification ◽  
Clinical Samples ◽  
Normal Plasma ◽  
Potential Biomarker ◽  
Significant Difference

Abstract Abstract 2890 Background: Multiple myeloma is an incurable and fatal hematologic malignancy. Recent gene microarray studies showed distinct gene expression profiles defining MM subgroups and their association with cytogenetic abnormalities and treatment outcome. However, aside from transcriptional control, a variety of post-transcriptional/post-translational modifications likely play an important role in regulating protein expression and function, and ultimately may prove informative for predicting tumor behavior. Objectives: We hypothesize that the protein profile in MM cells is different than normal plasma cells. Methodology: Normal plasma cells and myeloma cells were isolated using CD138 immune magnetic beads from bone marrow aspirates from healthy volunteers or patients with newly diagnosed MM, respectively. CD138+ cells were frozen and subsequently analyzed in one batch. Proteins were digested by trypsin. Tryptic peptides were injected onto an HPLC system and analyzed on a Thermo-Fisher LTQ mass spectrometer. Peptide identification and quantification were carried out using proprietary algorithms. Identified proteins were categorized into priority groups based on the quality of the peptide identification by tandem mass spectrometry. Proteins with significant changes in expression level were further analyzed by bioinformatics tools for the determination of the biological significance. Results: In the discovery phase of this study, 433 proteins were identified and their expression levels were quantitatively compared. 169 of these proteins demonstrated a significant difference between normal plasma cells and MM cells. Among the significantly changed proteins, 18 were identified and quantified with high confidence, and were therefore chosen for further validation. The identified proteins are known to be involved in the glycolysis/gluconeogenesis pathway, the oxidative phosphorylation pathway, cysteine metabolism and the pentose phosphate pathway. None of these proteins are known to be of prognostic value or being currently targeted for therapy in MM. A high-throughput LC/MS-based multiple-reaction-monitoring (MRM) assay for quantitative validation of these candidates with clinical samples is ongoing. To date, using the MRM assay, we were able to detect MRM peptides for 13 of the 18 targeted proteins in clinical samples. The quantification of these peptides will be further confirmed using a separate set of clinical samples. Conclusion: Significant differences in protein expression were observed between MM and normal plasma cells. The study presents an important step toward using proteomics as a tool to develop diagnostic and/or prognostic biomarkers in the clinical setting. However, both follow-up analytical and clinical validations are required before they can serve as disease-specific biomarkers. Disclosures: Abonour: Celgene: Membership on an entity's Board of Directors or advisory committees.

3' Untranslated Region (UTR) Alterations Are Frequently Targeted By MM-Related Mirnas and Affects the Clinical Outcome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4447-4447
Author(s):  
Mehmet K. Samur ◽  
Irtisha Singh ◽  
Lee Shih-Han ◽  
Adam Samuel Sperling ◽  
Mariateresa Fulciniti ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Clinical Outcome ◽  
Untranslated Region ◽  
High Throughput Sequencing ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Protein Localization ◽  
Median Frequency ◽  
Translation Efficiency ◽  
Normal Plasma

Abstract More than half of human genes use alternative cleavage and polyadenylation to generate alternative 3' untranslated region (3'UTR) isoforms that play a role in gene expression regulation. The 3' untranslated region (3'UTR) of mRNA contains elements that play regulatory roles in polyadenylation, localization, translation efficiency, and mRNA stability. Although relative contributions of different regulatory mechanisms remain poorly understood, several recent studies showed that alterations in 3'UTRs might affect protein localization as well as their interactions with other proteins. Here, we obtained global measurements of 3' UTR sequencing and RNA-seq in MM and normal plasma cells to study the effects of 3'UTR alterations in MM. Whole transcriptome sequencing (RNAseq) data from 420 uniformly treated newly diagnosed MM samples were compared with 18 normal plasma cell by using dynamic analyses of alternative PolyAdenylation and results were compared with alternative 3'UTR isoforms measured using 3'-seq, an established quantitative 3' end sequencing method from 15 samples pilot study. We observed ~10000 different isoforms with a median frequency of 297 (range 1-2495) altered 3'UTRs per sample. We observed 563 isoforms that have distal alternative poly A (APA) site and 449 isoforms that have proximal APA site compared to normal plasma cells in at least 10% of our patients. Enrichment analysis showed that short UTR genes are significantly targeted by miR-506, miR-133, miR-130, miR-27, miR-181 and miR-200 (FDR q-value < 0.05). We also observed that expression of 90 genes significantly increased between those samples with shorter UTR vs. regular UTR. Longer UTR genes are enriched in mir-124, mir-186, mir-200, mir-302, mir-495 and expression of 123 genes were significantly downregulated between long UTR and others. There were no tumor suppressor genes and 8 oncogenes in short UTR genes and 4 tumor suppressor and 14 oncogenes in longer UTR genes. Our results were confirmed using the 3'seq study which showed that 170 genes have longer UTR in MM compared to normal plasma cells and 187 genes have shorter UTR. ~60% of longer and ~65% of shorter UTR genes reported by 3'seq were also observed with RNAseq. Furthermore, we focused on common genes reported by both high-throughput sequencing methods and analyzed any connection between outcome and UTR shortening or lengthening. We observed 26 genes with altered UTR regions have impact on PFS or OS. In conclusion, we report significant alternate UTR usage, including intronic UTRs in MM affecting the disease biology and clinical outcome. Our data suggests the need to further investigate the molecular impact of alternate UTR usage and its relationship with miR in myeloma. Disclosures No relevant conflicts of interest to declare.

scholarly journals Extramedullary Plasmacytoma Diagnosed in an HIV-Positive Patient by an Unusual Clinical Presentation

2016 ◽  
Vol 2016 ◽  
pp. 1-5
Author(s):  
Paulo de Camargo Moraes ◽  
Luiz Alexandre Thomaz ◽  
Victor Angelo Martins Montalli ◽  
José Luiz Cintra Junqueira ◽  
Camila Maria Beder Ribeiro ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Clinical Presentation ◽  
Extramedullary Plasmacytoma ◽  
Positive Patient ◽  
Treatment Center ◽  
Hiv Positive ◽  
Rapid Progression ◽  
Oral Diseases ◽  
Infected Woman

The aim of this paper is to describe a case report of EMP in an HIV-positive patient. A 44-year-old, dark-skinned HIV-infected woman was referred to the Oral Diseases Treatment Center with a swelling at palate and left gingival fornix in the maxilla. Biopsy was taken and the oral lesion was diagnosed as EMP with well-differentiated plasma cells and restriction of the lambda light-chain. Skeletal survey was performed and no radiograph alterations were observed, thus supporting the diagnosis of EMP. Patient was referred to treatment and after two months of chemo and radiotherapy, an expanding lesion was observed in L5/S1 patient’s vertebrae. Biopsy of the spinal lesion was consistent with lymphoma with plasmocitary differentiation, supporting the diagnosis of multiple myeloma (MM). Regarding the medical history, the final diagnostic was an oral extramedullary plasmacytoma with rapid progression into multiple myeloma. It is crucial to emphasize the relevance of HIV infection as a risk factor for both aggressive clinical behavior and unusual clinical presentation of extramedullary plasmacytoma cases.

scholarly journals Extramedullary plasmacytoma of the tongue: A case report

2021 ◽  
Vol 2 (6) ◽  
Author(s):  
Leart Berdica ◽  
◽  
Teona Bushati ◽  
Alfred Aga ◽  
Emirjona Vajushi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Differential Diagnosis ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Histopathological Examination ◽  
English Literature ◽  
Extramedullary Plasmacytoma ◽  
Imaging Data ◽  
Plasma Cell Neoplasms ◽  
Extramedullary Plasmocytoma

Background: Tongue extramedullary plasmacytoma is a very rare pathology. Despite rare cases, extramedullary plasmacytoma should be considered as a differential diagnosis in case of a mass in the tongue. A total of 19 cases were reported with EMP in English literature along with the case we will address. It is characterized by a monoclonal neoplastic proliferation of plasma cells in the absence of multiple myeloma (MM). Histopathology and immunohistochemistry are very important for the diagnosis and differential diagnosis. Case presentation: The case we will describe is an 80-year-old lady from Albania who presents with a vegetative lesion in the form of a thick plate on the dorsal part of the tongue with dimensions 6 X 5 X 1.5 cm. A material of 0.5 cm diameter was taken from the lesion for the biopsy. After histopathological examination, immunohistochemical examinations, and after correlations with laboratory, clinical and imaging data, the diagnosis of extramedullary plasmacytoma of the tongue was reached. The patient underwent radiotherapy treatment. Conclusions: EMP is a rare tumor, accounting for 3% of plasma cell neoplasms and <1% of all head and neck tumors. The diagnosis of EMP, in this case, was reached with biopsy, immunohistochemistry, and the correlation with laboratory and imaging data. We will show the importance of biopsy along with immunohistochemistry in the diagnosis and differential diagnosis of extramedullary plasmocytoma of the tongue. Keywords: plasmacytoma; immunohistochemistry; biopsy; plasma cell. Abbreviations: EMP: Extramedullary plasmacytoma; MM: Multiple myeloma; Cm: centimeter

scholarly journals Genomic Basis of Multiple Myeloma Subtypes from the MMRF CoMMpass Study

2021 ◽  
Author(s):  
Sheri Skerget ◽  
Daniel Penaherrera ◽  
Ajai Chari ◽  
Sundar Jagannath ◽  
David S. Siegel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Plasma Cells ◽  
Hematological Malignancy ◽  
Therapeutic Option ◽  
Consensus Clustering ◽  
Newly Diagnosed ◽  
Loss Of Function ◽  
Serial Samples ◽  
Genomic Basis

Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The MMRF CoMMpass study is a longitudinal, observational clinical study of newly diagnosed multiple myeloma patients where tumor samples are characterized using whole genome, exome, and RNA sequencing at diagnosis and progression, and clinical data is collected every three months. Analyses of the baseline cohort identified genes that are the target of recurrent gain- and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option.

scholarly journals RAS Association Domain Family Member 4 (RASSF4): A New Potent Tumor Suppressor in Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2057-2057
Author(s):  
Eva De Smedt ◽  
Ken Maes ◽  
Stefan Verhulst ◽  
Hui Lui ◽  
Alboukadel Kassambara ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tumor Suppressor ◽  
Research Funding ◽  
Histone Deacetylase Inhibitors ◽  
Plasma Cells ◽  
Mapk Pathway ◽  
Dna Methyltransferases ◽  
Gene Set Enrichment Analysis ◽  
Domain Family ◽  
Potent Tumor

Abstract Multiple myeloma (MM) is a genetic highly heterogeneous plasma cell malignancy. In MM, the RAS/MAPK pathway is the most frequently mutated pathway, leading to aberrant MEK/ERK and PI3K/Akt signaling and thus stimulating MM cell growth and survival. Increasing evidence indicates that next to their classical oncogenic effects, RAS proteins can also induce growth inhibitory effects and apoptosis. These tumor suppressive effects are mainly mediated through the Ras-Association Domain Family (RASSF), a group of 10 RAS effector proteins (RASSF1-10) and numerous isoforms. Based on the localization of the Ras-association (RA) domain this family is further subdivided into two groups. RASSF1 to 6 harbor a C-terminal RA domain and are termed the classical group, while RASSF7-10 contain a N-terminal RA domain and are referred to as non-classical RASSF proteins. The classical RASSF members also carry a SARAH domain on the C-terminus, allowing the RASSF proteins to bind each other and the mammalian sterile 20-like kinases MST and MST-2. Currently, no data about the biological role of RASSF proteins in the pathogenesis of MM is available. Here, we first investigated the expression of the classical RASSF proteins RASSF1-6 in MM using publically available gene expression profiling data of 2 independent newly diagnosed patient cohorts (namely the Heidelberg-Montpellier and the UAMS-TT2 cohort) and 1 cohort of relapsed patients (Mulligan-cohort). We report that RASSF4 was the only classical RASSF protein that was consistently found downregulated in MM cells compared to normal bone marrow plasma cells, correlating with a bad prognosis in all cohorts. Treatment with epigenetic modulating agents including histone deacetylase inhibitors (HDACi) and DNA methyltransferases inhibitors significantly increased RASSF4 expression both in vitro and in vivo, indicating that RASSF4 downregulation in MM is due to epigenetic silencing. Forced RASSF4 expression induced a strong G2-phase arrest and caspase-3 mediated apoptosis in human MM cell lines and strongly reduced the viability of primary CD138+ MM cells. Moreover, RASSF overexpression significantly reduced in vivotumor growth. In addition, we showed RASSF4-MST1 binding and the activation of the downstream signaling pathways JNK/Jun, p38 and p53. RNA sequencing and gene set enrichment analysis following forced RASSF4 expression furthermore revealed downregulation of genes involved in protein metabolism, the unfolded protein response and translation. RASSF4 overexpression also sensitized MM cells to the proteasome inhibitor bortezomib, the specific MEK1/2 inhibitor trametinib and the ROS inducer Prima-1Met. Consequently, combining trametinib with HDACi, e.g. panobinostat, resulted in very strong synergistic anti-MM effects. In conclusion, we identified RASSF4 as a new potent tumor suppressor in MM that is epigenetically silenced in malignant plasma cells and provide a rationale for testing novel therapeutic strategies enhancing RASSF4 expression (using HDACi or gene therapy) in combination with MEK/ERK inhibitors and bortezomib. Disclosures Hose: Takeda: Other: Travel grant; EngMab: Research Funding; Sanofi: Research Funding.

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