scholarly journals Paired-Box 5 Positivity Related to High MIPI Score Predicts Shorter Overall Survival in Mantle Cell Lymphoma Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4481-4481
Author(s):  
Yang Han ◽  
Xin Zhang ◽  
Yu Nie ◽  
Yujie Jiang ◽  
Xiaohui Sui ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Poor Prognosis ◽  
Clinical Characteristics ◽  
Cell Lymphoma ◽  
Positive Expression ◽  
Mantle Cell

Abstract Introduction: Mantle cell lymphoma (MCL) is a sub-type of B-cell non-Hodgkin Lymphomas (NHL) that characterized by a heterogenous clinical course and poor prognosis. The transcription factor paired-box 5 (PAX5) is associated with B cell normal differentiation and development. Herein, we aim to explore both the prognostic factors and the role of PAX5 expression in MCL patients from single-center, which can provide theoretical guidance for clinical practice. Methods: The data of 80 MCL patients admitted to Shandong Provincial Hospital from October 2006 to April 2020 were collected to be analyzed. Kaplan-Meier method and univariate and multivariate cox analysis was used to analyze the correlation between overall survival and prognostic factors. Chi-square test, Pearson and Fisher correlation analysis were performed for statistical analysis of clinical features and experimental indicators. *p value<0.05 indicated that the difference was statistically significant. Immunohistochemistry (IHC) was used to label the protein expression. Gene expression profiles were applied to analyze the discrepancy of PAX5 mRNA expression in some lymphoma types. Results: Clinical characteristics of all MCL patients were analyzed. PAX5 expression was identified by IHC in this study: the positive expression rate of PAX5 in all MCL patients was 60% (Figure 1A). The mRNA expression level of PAX5 was obviously elevated in MCL specimens than in normal group compared with other groups (p= 0.034) (Figure 1B). Besides, CD5, CD19, CD22, CD38, CD79α, CD79β and SOX11 were shown co-expressed with PAX5 by string database analysis (Figure 1C). PAX5-related genes were found mainly enriched in lymphocyte activation, B cell proliferation and NOTCH1 signaling pathway (Figure 1D). As is shown in Figure 1E-I, MIPI score (≥6), median to high risk group, high β2-MG level (≥2.65 mg/L), ECOG score (≥2), and splenomegaly were associated with adverse survival (p= 0.006, 0.030, 0.001, 0.019 and 0.001 respectively). The positive expression of PAX5 indicated a shorter overall survival in MCL patients (p= 0.024, Figure 1G). Positive PAX5 expression was associated with international prognostic index (MIPI) score (p= 0.038), high risk stratification (p= 0.006), WBC count (p= 0.024), and increased β2-microglobulin level (p= 0.008). MCL patients with PAX5-positive expression, high level of β2-MG level (≥2.65 mg/L), splenomegaly correlated with a poorer OS (p=0.002, and 0.004 respectively, Figure 1K, L). In patients with PAX5-negative expression, splenomegaly also indicated poor prognosis (p= 0.030, Figure 1M). Furthermore, among patients with high MIPI scores, PAX5-positive MCL patients had a shorter overall survival than PAX5-negative patients (p= 0.016, Figure N, O). Multivariate analysis showed that positive PAX was an independent prognostic factor for poor survival of MCL (p= 0.035). Conclusions: The positive expression of PAX5 in immunohistochemistry may be a factor contributing to the poor prognosis of MCL patients, which is correlated with clinical characteristics and laboratory indicators to a certain extent. Our results the role of PAX5 positivity in MCL and provide clinical guidance for clinical prognostic risk assessment and treatment strategy selection. Keywords: Mantle cell lymphoma; Paired-box 5; Prognosis; Immunohistochemistry Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Artificial Intelligence Analysis of Gene Expression Predicted the Overall Survival of Mantle Cell Lymphoma and a Large Pan-Cancer Series

Healthcare ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 155
Author(s):  
Joaquim Carreras ◽  
Naoya Nakamura ◽  
Rifat Hamoudi
Keyword(s):  
Artificial Intelligence ◽  
Overall Survival ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
High Accuracy ◽  
Gene Set Enrichment Analysis ◽  
Intelligence Analysis ◽  
Mantle Cell ◽  
Pan Cancer

Mantle cell lymphoma (MCL) is a subtype of mature B-cell non-Hodgkin lymphoma characterized by a poor prognosis. First, we analyzed a series of 123 cases (GSE93291). An algorithm using multilayer perceptron artificial neural network, radial basis function, gene set enrichment analysis (GSEA), and conventional statistics, correlated 20,862 genes with 28 MCL prognostic genes for dimensionality reduction, to predict the patients’ overall survival and highlight new markers. As a result, 58 genes predicted survival with high accuracy (area under the curve = 0.9). Further reduction identified 10 genes: KIF18A, YBX3, PEMT, GCNA, and POGLUT3 that associated with a poor survival; and SELENOP, AMOTL2, IGFBP7, KCTD12, and ADGRG2 with a favorable survival. Correlation with the proliferation index (Ki67) was also made. Interestingly, these genes, which were related to cell cycle, apoptosis, and metabolism, also predicted the survival of diffuse large B-cell lymphoma (GSE10846, n = 414), and a pan-cancer series of The Cancer Genome Atlas (TCGA, n = 7289), which included the most relevant cancers (lung, breast, colorectal, prostate, stomach, liver, etcetera). Secondly, survival was predicted using 10 oncology panels (transcriptome, cancer progression and pathways, metabolic pathways, immuno-oncology, and host response), and TYMS was highlighted. Finally, using machine learning, C5 tree and Bayesian network had the highest accuracy for prediction and correlation with the LLMPP MCL35 proliferation assay and RGS1 was made. In conclusion, artificial intelligence analysis predicted the overall survival of MCL with high accuracy, and highlighted genes that predicted the survival of a large pan-cancer series.

Prognostic role of SOX11 in a population-based cohort of mantle cell lymphoma

Blood ◽  
2012 ◽  
Vol 119 (18) ◽  
pp. 4215-4223 ◽  
Author(s):  
Lina Nygren ◽  
Stefanie Baumgartner Wennerholm ◽  
Monika Klimkowska ◽  
Birger Christensson ◽  
Eva Kimby ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Eastern Cooperative Oncology Group ◽  
Population Based ◽  
Prognostic Role ◽  
P53 Expression ◽  
Mantle Cell ◽  
Indolent Disease

Abstract The prognostic role of the transcription factor SOX11 in mantle cell lymphoma (MCL) is controversial. We investigated prognostic markers in a population-based cohort of 186 MCL cases. Seventeen patients (9%) did not require any therapy within the first 2 years after diagnosis and were retrospectively defined as having an indolent disease. As expected, indolent MCL had less frequent B symptoms and extensive nodal involvement and 88% of these cases expressed SOX11. In our cohort 13 cases (7.5%) lacked nuclear SOX11 at diagnosis. SOX11− MCL had a higher frequency of lymphocytosis, elevated level of lactate dehydrogenase (LDH), and p53 positivity. The overall survival in the whole cohort, excluding 37 patients receiving autologous stem cell transplantation, was 3.1 year and in patients with indolent or nonindolent disease, 5.9 and 2.8 years, respectively (P = .004). SOX11− cases had a shorter overall survival, compared with SOX11+ cases, 1.5 and 3.2 years, respectively (P = .014). In multivariate analysis of overall survival, age > 65 (P = .001), Eastern Cooperative Oncology Group score ≥ 2 (P = .022), elevated LDH level (P = .001), and p53 expression (P = .001) remained significant, and SOX11 lost significance. We conclude that most indolent MCLs are SOX11+ and that SOX11 cannot be used for predicting an indolent disease course.

Somatic Mutation and Isotype Switch Events Outside Igv Gene Loci Provide New Evidence for a Role of Antigenic Challenge in Mantle Cell Lymphoma Etiology

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2647-2647
Author(s):  
Sandrine Roulland ◽  
Nathalie Jouve ◽  
Agnes Bru ◽  
Marie-Helene Delfau-Larue
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
High Rate ◽  
Chain Gene ◽  
Functional Allele ◽  
Antigenic Challenge ◽  
Mantle Cell

Abstract Mantle cell lymphoma (MCL) represents 5-10% of B-cell lymphomas and generally exhibits an aggressive clinical behavior. t(11;14) translocation, the genetic hallmark and early initiating event of MCL pathogenesis, lead to the constitutive CCND1 expression and consequently to cell-cycle deregulation. However, t(11;14) is also present in the blood from rare healthy individuals indicating that alone the t(11;14) is not sufficientfor malignant transformation. It has long been assumed in MCL that t(11;14)+ cells were actually carried by circulating naive and antigen-inexperienced B-cells. Yet, several reports, including long-term persistence of t(11;14)+ cells in lymphoma free-patients, biased immunoglobulin heavy variable chain gene (IgVH) repertoire and evidence of subset of cases with mutated IgVH genes led us to question this model and further investigate the role of antigenic challenge in MCL etiologic origin. As a first approach, we sought to determine the class-switch recombination (CSR) status of t(11;14)+ cells in MCL patients. CSR, as somatic hypermutation (SHM), are diversification mechanisms of the B cell receptor induced upon antigen encounter in the germinal center (GC) reaction, and absent in naive cells. Evidence for ongoing switch events in MCL has been previously reported with detection of mature switch transcripts, however in MCL cells, sIgM(D) expression remains clearly evident suggesting that effective deletional switch events occur infrequently on the functional allele. To characterize CSR in t(11;14)+ cells, we thus took advantage of their unique BCL1/IGH translocation signature assuming that BCL1/IGH fusions do not prevent CSR to occur on the downstream constant region of the IGH locus. Using 2 long-range PCR assays designed to amplify unswitched BCL1/Sµ and switched BCL1/Sγ regions, DNA from 30 MCL patients differing by their IgVH status were tested. Of the MCL cases, we confirmed that 7 of 30 (23%) were unmutated (UM, 100% germline homology) and 23 of 30 (77%) were mutated (M), considering as mutated all cases exhibiting any level of SHM (ranging from minimal: >0.3% to high rate: 7.0%). Although mutated BCRs were common in most MCL cases, we found that only 1 out of 30 MCL cases underwent CSR to IgG on the non-productive, translocated allele. Accordingly, this case carried a mutated IgVH gene with 97.5% germline identity in line with a GC/antigen-experienced signature of the tumor cells. Contrary to SHM events of the IgVH gene region, CSR deletional events appeared very infrequent in the bulk of MCL cells both on the functional and translocated allele, contrasting from findings in other GC-derived non-Hodgkin lymphomas where the same selective pressure to maintain a sIgM is accompanied by deletional switch events on the non-functional allele. To get more insights into a role of antigenic drive in MCL and AID targeting outside the VH gene loci, we next evaluated the clonal evolution of t(11;14)+ cells from 11 MCL cases (2 UM and 9 M) by analyzing SHM in the Sμ region on the translocated allele using sequencing of LR-PCR amplicons (with 2 subclones/patient). We found that 63% (7 out of 11) of BCL1/IGH clones display significant levels of SHM in the Sµ together with intra-Sµ indels (2/11) compatible with off-target AID-mediated events linked to chronic(?) antigen encounter. In addition, we found a good correlation between mutated BCR and the SHM levels in Sμ regions for a given patient. Importantly, in one instance subclones from a MCL case displayed intraclonal diversification (despite the fact that the expected rate of SHM is much lower in the Sµ region than in the IgVH region), indicative of an ongoing AID activity at least in a subset of MCL cases. In conclusion, we found that CSR events, although detectable in some MCL cases, do not appear to participate predominantly or to be selected during MCL lymphomagenesis. By contrast, analysis of SHM profiles both on the functional and the non-functional translocated allele provide evidence for an active AID activity in MCL cells inside and outside V-gene loci, highlighting the propensity of some t(11;14)+ clones to acquire a complementary oncogenic hit over time as a result of recurrent antigen challenge. Disclosures No relevant conflicts of interest to declare.

scholarly journals Phospho-proteomic analysis of mantle cell lymphoma cells suggests a pro-survival role of B-cell receptor signaling

2011 ◽  
Vol 34 (2) ◽  
pp. 141-153 ◽  
Author(s):  
Chiara Pighi ◽  
Ting-Lei Gu ◽  
Irene Dalai ◽  
Stefano Barbi ◽  
Claudia Parolini ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Proteomic Analysis ◽  
Cell Lymphoma ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Mantle Cell ◽  
B Cell Receptor Signaling ◽  
Cell Receptor Signaling

scholarly journals Non-Coding RNAs in Normal B-Cell Development and in Mantle Cell Lymphoma: From Molecular Mechanism to Biomarker and Therapeutic Agent Potential

2021 ◽  
Vol 22 (17) ◽  
pp. 9490
Author(s):  
Olga Kersy ◽  
Mali Salmon-Divon ◽  
Ofer Shpilberg ◽  
Oshrat Hershkovitz-Rokah
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Cell Development ◽  
B Cell Development ◽  
Cellular Growth ◽  
Aberrant Expression ◽  
Mantle Cell ◽  
Non Coding Rnas

B-lymphocytes are essential for an efficient immune response against a variety of pathogens. A large fraction of hematologic malignancies are of B-cell origin, suggesting that the development and activation of B cells must be tightly regulated. In recent years, differentially expressed non-coding RNAs have been identified in mantle cell lymphoma (MCL) tumor samples as opposed to their naive, normal B-cell compartment. These aberrantly expressed molecules, specifically microRNAs (miRNAs), circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs), have a role in cellular growth and survival pathways in various biological models. Here, we provide an overview of current knowledge on the role of non-coding RNAs and their relevant targets in B-cell development, activation and malignant transformation, summarizing the current understanding of the role of aberrant expression of non-coding RNAs in MCL pathobiology with perspectives for clinical use.

scholarly journals The role of B cell antigen receptors in mantle cell lymphoma

2017 ◽  
Vol 10 (1) ◽  
Author(s):  
Michael Fichtner ◽  
Martin Dreyling ◽  
Mascha Binder ◽  
Martin Trepel
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Antigen Receptors ◽  
Cell Antigen ◽  
Mantle Cell

Cytogenetic Aberrations Characterize Mantle Cell Lymphoma With Bone Marrow Involvement and Provide The Most Important Prognostic Information

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5067-5067
Author(s):  
Shuhua Yi ◽  
Zengjun Li ◽  
Gang An ◽  
Chengwen Li ◽  
Dehui Zou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Prognostic Factors ◽  
High Risk ◽  
Mantle Cell Lymphoma ◽  
Clinical Characteristics ◽  
Cell Lymphoma ◽  
Risk Group ◽  
Bone Marrow Involvement ◽  
Cytogenetic Aberrations ◽  
Mantle Cell

Abstract Introduction The clinical characteristics and cytogenetic aberrations of mantle cell lymphoma (MCL) is well described in the West, but not in China, and also not mentioned in patients with bone marrow involvement (BMI). The aim of this study was to characterize the clinical and cytogenetic feature of Chinese patients with MCL. Methods During the period July 2003 through November 2012, 50 MCL patients with BMI were diagnosed at our Hospital. Cytogenetic aberrations were detected by FISH on bone marrow cells, using a panel probes including Rb1, TP53, ATM and c-MYC. Results The median age of the 50 patients was 55.5 years at diagnosis, with 38 male patients (76%). Eighteen patients had B symptom, 36 patients with splenomegaly, while 4 patients had hepatomegaly. Twenty-four of the forty-five patients had elevated serum LDH. According to MIPI system, 13 patients (27.7%) were classified into medium risk group, while 34 patients (72.3%) in the high risk prognosis group. In aspect of the cytogenetic aberrations, eleven of forty-two patients (26.2%) had Rb-1 deletion, 7/39 patients (17.9%) with ATM deletion, 16/42 patients (38.1%) with TP53 deletion, while 15/37 patients (40.5%) had c-MYC abnormality, including amplification and translocation. With a median follow-up of 21.5 months, the median estimated progression-free survival (PFS) was 15 months (95% CI 8.6-21.4), and the median estimated overall survival (OS) was 27 months (95% CI 17.5-36.5). Using the Kaplan-Meier method, the MIPI high risk group, deletion of Rb-1, ATM, TP53 and c-MYC abnormality were the adverse prognostic factors for PFS, while deletion of Rb-1, ATM, TP53 and c-MYC abnormality predicted the worse OS in the univariate analysis. All other clinical characteristics did not significantly influence the PFS and OS(p>0.05). TP53 deletion and c-MYC abnormality were the independent prognostic factors for both of PFS and OS in the multivariate analysis. Conclusions The outcome of MCL with BMI was poor. TP53 deletion and c-MYC abnormality were common in MCL with BMI and represented the worst factors for survival. Disclosures: No relevant conflicts of interest to declare.

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