miRNA expression profiling of CD20+ plasma cell myeloma (PCM): Upregulation of miR-155 shedding new insight into disease biology and clinicopathologic behavior.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8108-8108
Author(s):  
Ravindra Kolhe ◽  
Anand P. Jillella ◽  
Kavita Natrajan ◽  
Farrukh Tauseef Awan ◽  
Elizabeth Manaloor ◽  
...  
Keyword(s):  
B Cell ◽  
Plasma Cell ◽  
Mirna Expression ◽  
Cell Activation ◽  
Expression Profiles ◽  
Prognostic Significance ◽  
B Cell Lymphoma ◽  
Sh2 Domain ◽  
Clinicopathological Parameters ◽  
B Cell Differentiation

8108 Background: Up to15-20% of patients with PCM have expression of CD20, although the significance of this remains unclear. The prognostic significance of CD20 expression in PCM is unclear. Recently, a class of noncoding RNAs, miRNAs, were identified as critical gene regulators in cell growth, disease, and development. Our study investigates importance of miRNAs in cases of CD20+ PCM and correlates them with clinicopathological parameters. Methods: The miRNA expression profile of CD20+ PCM (n=6), diffuse large B cell lymphoma (DLBCL) (n=6), and CD20 negative PCM (n=8) were evaluated using the Affeymertrix miRNA microarray platform on GeneChip miRNA 2.0 array in paraffin-embedded samples. After hybridization and data acquisition, we used Partek Genomics Suite software for RMA normalization and to determine statistically significant differences in miRNA expression between experimental groups by ANOVA and pairwise comparisons (two-sided α=0.05). Results: miRNA expression profiles of CD20+ PCM, show upto >4 times upregulation of 7 miRNAs and downregulation of 8 miRNAs. miR-155, the miRNA upregulated in various B cell lymphomas and plays a key role in the lymphomagenesis, was amongst the highest miRNAs that were upregulated. Conclusions: miR-155 is known to repress SH2-domain containing inositol-5-phosphatase-1 (SHIP-1), which is a critical phosphatase that negatively down modulates AKT pathway and has functions during normal B-cell development. Physiologically, miR-155 is upregulated during B-cell activation upon antigen stimulation and so plays a role in antibody class switching and plasma cell formation. We propose that this overexpression of miR-155 in CD20+ PCM unblocks AKT activity, inducing cell proliferation and may explain some of the immunophenotypic behavior of CD20+ PCM. This work is intriguing for the new information it provides about the role of miR-155 in CD20+ PCM. Furthermore, the phenotype of miR-155+ve CD20+ PCM might ultimately provide new insights into regulation of poorly understood steps in B cell differentiation and maturation into plasma cell and more importantly the clinicopathological behavior of this entity.

Mir-21 Is Over Expressed in Aggressive SMZL

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 624-624
Author(s):  
Marie Bouteloup ◽  
Aurélie Verney ◽  
Lucile Baseggio ◽  
Evelyne Callet-Bauchu ◽  
Pascale Felman ◽  
...  
Keyword(s):  
B Cell ◽  
Mirna Expression ◽  
Marginal Zone ◽  
B Cell Lymphoma ◽  
Mirna Expression Profile ◽  
Splenic Marginal Zone Lymphoma ◽  
B Cell Differentiation ◽  
Mirna Expression Pattern ◽  
Oncogenic Pathways ◽  
Histological Transformation

Abstract Within the group of indolent B cells lymphomas derived from cells of the marginal zone, the pathogenesis of Splenic Marginal Zone Lymphoma (SMZL) remains incompletely characterized, in contrast to MALT lymphoma. However numerous findings recently contributed to a better description of this lymphoma, including its possible association with hepatitis C and the recurrence of 7q deletion. Furthermore, the peculiar pattern of Ig genes mutations and the biased usage of some segments (IGHV1-2) is suggestive of a T-independent Ag driven proliferation, at least at initial steps. The clinical heterogeneity is also marked with a lack of reproducible prognostic factors able to characterize the cases with a more aggressive course or histological transformation. MicroRNA (miRNA) are small non-coding RNA that have a post transcriptional regulation role by inhibiting translation of mRNA in protein and their abnormal expression was already found to contribute to the oncogenesis of various leukemias and lymphomas. The aim of the study was then to identify a miRNA profile of SMZL and to assess if specific miRNAs were associated with biological or clinical characteristics. MiRNA expression profile of SMZL was obtained by quantitative RT-PCR technology (Taqman microRNA Assays Human Panel, Applied Biosystems) which enabled to analyze 365 miRNAs. Six frozen spleen specimens of SMZL (including 2 cases with histological transformation) and 5 frozen specimens of non tumoral spleen (traumatic) were used to compare miRNA levels of expression (2−□□Ct method). Out of these 365 miRNAs, 95 were found to be reproducibly detectable in those samples and were further analyzed. Three miRNA were uniformly overexpressed in SMZL samples as compared to non tumor samples: miR-155 (mean fold change = 3.1), miR-451 (mean = 2.37), miR-486 (mean = 2.7). Conversly, 4 miRNAs were uniformly underexpressed: miR-127 (mean = 0.32), miR-139 (mean = 0.32), miR-335 (mean = 0.26), miR-411 (mean = 0.25). Interestingly, 1 miRNA, miR-21 was specifically found overexpressed only in the 2 transformed cases of SMZL (mean = 3.49) in comparison with the 4 non transformed cases (mean = 0.94). Those results were confirmed in a larger cohort of SMZL patients using a simplex real time PCR (Taqman microRNA Assays Human, Applied Biosystems) on frozen or paraffin embedded samples with a specific overexpression of miR-21 in 10 transformed cases (mean = 14.4), absent in the 6 non transformed cases (mean = 0.9) (Mann Whitney test: p =.0022). MiR-155 plays a key role in B cell differentiation and was already found overexpressed in other lymphomas subtypes. Little is know about the other miR overexpressed except for MiR- 21. MiR-21 is commonly overexpressed in solid tumors and the level of its expression is correlated in tumor growth and metastatic dissemination. It was also found overexpressed in chronic lymphocytic leukaemia and DLBCL (diffuse large B cell lymphoma). In opposite to DLBCL, our results seem to link miR-21’s overexpression with aggressive forms of SMZL. MiR-21 regulates multiple genes associated with apoptosis, migration and invasiveness. Altogether, these data points towards a specific miRNA expression pattern in SMZL and suggests that miR-21 could regulate important oncogenic pathways in transformed SMZL lymphomas.

miRNA expression in diffuse large B-cell lymphoma treated with chemoimmunotherapy

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 1034-1040 ◽  
Author(s):  
Santiago Montes-Moreno ◽  
Nerea Martinez ◽  
Beatriz Sanchez-Espiridión ◽  
Ramon Díaz Uriarte ◽  
Maria Elena Rodriguez ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
B Cell ◽  
Mirna Expression ◽  
Cox Regression ◽  
Cell Lymphoma ◽  
Expression Profiles ◽  
Test Group ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL) prognostication requires additional biologic markers. miRNAs may constitute markers for cancer diagnosis, outcome, or therapy response. In the present study, we analyzed the miRNA expression profile in a retrospective multicenter series of 258 DLBCL patients uniformly treated with chemoimmunotherapy. Findings were correlated with overall survival (OS) and progression-free survival (PFS). miRNA and gene-expression profiles were studied using microarrays in an initial set of 36 cases. A selection of miRNAs associated with either DLBCL molecular subtypes (GCB/ABC) or clinical outcome were studied by multiplex RT-PCR in a test group of 240 cases with available formalin-fixed, paraffin-embedded (FFPE) diagnostic samples. The samples were divided into a training set (123 patients) and used to derive miRNA-based and combined (with IPI score) Cox regression models in an independent validation series (117 patients). Our model based on miRNA expression predicts OS and PFS and improves upon the predictions based on clinical variables. Combined models with IPI score identified a high-risk group of patients with a 2-year OS and a PFS probability of < 50%. In summary, a precise miRNA signature is associated with poor clinical outcome in chemoimmunotherapy-treated DLBCL patients. This information improves upon IPI-based predictions and identifies a subgroup of candidate patients for alternative therapeutic regimens.

scholarly journals Differentiation stage–specific expression of microRNAs in B lymphocytes and diffuse large B-cell lymphomas

Blood ◽  
2009 ◽  
Vol 113 (16) ◽  
pp. 3754-3764 ◽  
Author(s):  
Raquel Malumbres ◽  
Kristopher A. Sarosiek ◽  
Elena Cubedo ◽  
Jose W. Ruiz ◽  
Xiaoyu Jiang ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cell ◽  
Mirna Expression ◽  
Cell Transformation ◽  
B Cell Lymphoma ◽  
Malignant Cell ◽  
B Cell Differentiation ◽  
Specific Expression ◽  
B Cell Subsets ◽  
Large B Cell

Abstract miRNAs are small RNA molecules binding to partially complementary sites in the 3′-UTR of target transcripts and repressing their expression. miRNAs orchestrate multiple cellular functions and play critical roles in cell differentiation and cancer development. We analyzed miRNA profiles in B-cell subsets during peripheral B-cell differentiation as well as in diffuse large B-cell lymphoma (DLBCL) cells. Our results show temporal changes in the miRNA expression during B-cell differentiation with a highly unique miRNA profile in germinal center (GC) lymphocytes. We provide experimental evidence that these changes may be physiologically relevant by demonstrating that GC-enriched hsa-miR-125b down-regulates the expression of IRF4 and PRDM1/BLIMP1, and memory B cell–enriched hsa-miR-223 down-regulates the expression of LMO2. We further demonstrate that although an important component of the biology of a malignant cell is inherited from its nontransformed cellular progenitor—GC centroblasts—aberrant miRNA expression is acquired upon cell transformation. A 9-miRNA signature was identified that could precisely differentiate the 2 major subtypes of DLBCL. Finally, expression of some of the miRNAs in this signature is correlated with clinical outcome of uniformly treated DLBCL patients.

scholarly journals The AP-1 transcription factor Fra1 inhibits follicular B cell differentiation into plasma cells

2014 ◽  
Vol 211 (11) ◽  
pp. 2199-2212 ◽  
Author(s):  
Bettina Grötsch ◽  
Sebastian Brachs ◽  
Christiane Lang ◽  
Julia Luther ◽  
Anja Derer ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Cell Activation ◽  
Plasma Cells ◽  
Regulatory Gene ◽  
B Cell Differentiation ◽  
Plasma Cell Differentiation ◽  
Activated B Cells

The cornerstone of humoral immunity is the differentiation of B cells into antibody-secreting plasma cells. This process is tightly controlled by a regulatory gene network centered on the transcriptional repressor B lymphocyte–induced maturation protein 1 (Blimp1). Proliferation of activated B cells is required to foster Blimp1 expression but needs to be terminated to avoid overshooting immune reactions. Activator protein 1 (AP-1) transcription factors become quickly up-regulated upon B cell activation. We demonstrate that Fra1, a Fos member of AP-1, enhances activation-induced cell death upon induction in activated B cells. Moreover, mice with B cell–specific deletion of Fra1 show enhanced plasma cell differentiation and exacerbated antibody responses. In contrast, transgenic overexpression of Fra1 blocks plasma cell differentiation and immunoglobulin production, which cannot be rescued by Bcl2. On the molecular level, Fra1 represses Blimp1 expression and interferes with binding of the activating AP-1 member c-Fos to the Blimp1 promoter. Conversely, overexpression of c-Fos in Fra1 transgenic B cells releases Blimp1 repression. As Fra1 lacks transcriptional transactivation domains, we propose that Fra1 inhibits Blimp1 expression and negatively controls plasma cell differentiation through binding to the Blimp1 promoter. In summary, we demonstrate that Fra1 negatively controls plasma cell differentiation by repressing Blimp1 expression.

scholarly journals Hyaluronate-CD44 Interactions Can Induce Murine B-Cell Activation

Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2901-2908 ◽  
Author(s):  
Asimah Rafi ◽  
Mitzi Nagarkatti ◽  
Prakash S. Nagarkatti
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Critical Role ◽  
Surface Glycoprotein ◽  
B Cell Differentiation ◽  
B Cell Activation ◽  
Cell Surface Glycoprotein ◽  
Immunodeficient Mice

Abstract CD44 is a widely distributed cell surface glycoprotein whose principal ligand has been identified as hyaluronic acid (HA), a major component of the extracellular matrix (ECM). Recent studies have demonstrated that activation through CD44 leads to induction of effector function in T cells and macrophages. In the current study, we investigated whether HA or monoclonal antibodies (MoAbs) against CD44 would induce a proliferative response in mouse lymphocytes. Spleen cells from normal and nude, but not severe combined immunodeficient mice, exhibited strong proliferative responsiveness to stimulation with soluble HA or anti-CD44 MoAbs. Furthermore, purified B cells, but not T cells, were found to respond to HA. HA was unable to stimulate T cells even in the presence of antigen presenting cells (APC) and was unable to act as a costimulus in the presence of mitogenic or submitogenic concentrations of anti-CD3 MoAbs. In contrast, stimulation of B cells with HA in vitro, led to B-cell differentiation as measured by production of IgM antibodies in addition to increased expression of CD44 and decreased levels of CD45R. The fact that the B cells were responding directly to HA through its binding to CD44 and not to any contaminants or endotoxins was demonstrated by the fact that F(ab)2 fragments of anti-CD44 MoAbs or soluble CD44 fusion proteins could significantly inhibit the HA-induced proliferation of B cells. Also, HA-induced proliferation of B cells was not affected by the addition of polymixin B, and B cells from lipopolysaccharide (LPS)-unresponsive C3H/HeJ strain responded strongly to stimulation with HA. Furthermore, HA, but not chondroitin-sulfate, another major component of the ECM, induced B-cell activation. It was also noted that injection of HA intraperitoneally, triggered splenic B cell proliferation in vivo. Together, the current study demonstrates that interaction between HA and CD44 can regulate murine B-cell effector functions and that such interactions may play a critical role during normal or autoimmune responsiveness of B cells.

Prognostic significance of CD30 expression in diffuse large B cell lymphoma: A systematic review with meta‐analysis

2021 ◽  
Author(s):  
Carla Isabelly Rodrigues‐Fernandes ◽  
Lucas Guimarães Abreu ◽  
Raghu Radhakrishnan ◽  
Danyel Elias da Cruz Perez ◽  
Gleyson Kleber Amaral‐Silva ◽  
...  
Keyword(s):  
Systematic Review ◽  
B Cell ◽  
Cell Lymphoma ◽  
Meta Analysis ◽  
Prognostic Significance ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals Circulating long non-coding RNAs HOTAIR, Linc-p21, GAS5 and XIST expression profiles in diffuse large B-cell lymphoma: association with R-CHOP responsiveness

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mahmoud A. Senousy ◽  
Aya M. El-Abd ◽  
Raafat R. Abdel-Malek ◽  
Sherine M. Rizk
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Expression Profiles ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Diagnostic Tools ◽  
Large B Cell Lymphoma ◽  
Non Coding Rnas ◽  
Large B Cell

AbstractThe reliable identification of diffuse large B-cell lymphoma (DLBCL)-specific targets owns huge implications for its diagnosis and treatment. Long non-coding RNAs (lncRNAs) are implicated in DLBCL pathogenesis; however, circulating DLBCL-related lncRNAs are barely investigated. We investigated plasma lncRNAs; HOTAIR, Linc-p21, GAS5 and XIST as biomarkers for DLBCL diagnosis and responsiveness to R-CHOP therapy. Eighty-four DLBCL patients and thirty-three healthy controls were included. Only plasma HOTAIR, XIST and GAS5 were differentially expressed in DLBCL patients compared to controls. Pretreatment plasma HOTAIR was higher, whereas GAS5 was lower in non-responders than responders to R-CHOP. Plasma GAS5 demonstrated superior diagnostic accuracy (AUC = 0.97) whereas a panel of HOTAIR + GAS5 superiorly discriminated responders from non-responders by ROC analysis. In multivariate analysis, HOTAIR was an independent predictor of non-response. Among patients, plasma HOTAIR, Linc-p21 and XIST were correlated. Plasma GAS5 negatively correlated with International Prognostic Index, whereas HOTAIR positively correlated with performance status, denoting their prognostic potential. We constructed the lncRNAs-related protein–protein interaction networks linked to drug response via bioinformatics analysis. In conclusion, we introduce plasma HOTAIR, GAS5 and XIST as potential non-invasive diagnostic tools for DLBCL, and pretreatment HOTAIR and GAS5 as candidates for evaluating therapy response, with HOTAIR as a predictor of R-CHOP failure. We provide novel surrogates for future predictive studies in personalized medicine.

scholarly journals Advances and Perspectives in the Treatment of B-Cell Malignancies

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2266
Author(s):  
Marta Cuenca ◽  
Victor Peperzak
Keyword(s):  
Cell Differentiation ◽  
B Cell ◽  
Plasma Cell ◽  
Heterogeneous Group ◽  
B Cell Differentiation ◽  
B Cell Lymphomas ◽  
B Cell Malignancies ◽  
Plasma Cell Dyscrasias

B-cell malignancies arise from different stages of B-cell differentiation and constitute a heterogeneous group of cancers including B-cell lymphomas, B-cell leukemias, and plasma cell dyscrasias [...]

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