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
Joaquim Carreras ◽  
Naoya Nakamura ◽  
Rifat Hamoudi

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.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 287-287
Patricia Perez Galan ◽  
Helena Mora Jensen ◽  
Marc A Weniger ◽  
Colby M Chapman ◽  
Poching Liu ◽  

Abstract Abstract 287 Mantle cell lymphoma (MCL) is a lymphoproliferative disorder of mature B-cells with an aggressive course and short survival. The proteasome inhibitor bortezomib (BZM) induces clinical responses in up to 50% of patients. Conversely, in half of the cases the lymphoma cells are intrinsically resistant or rapidly develop resistance to BZM. To investigate the mechanisms of BZM resistance, we generated HBL2 and JEKO bortezomib resistant (HBL2-BR, JEKO-BR) derivative lines by continuous culture in sub-lethal concentrations of BZM. After several months, clones of HBL2-BR and JEKO-BR were obtained showing BZM IC50 at 48h of 41.6 and 44.6 nM, compared to 6 and 4.9 nM for the respective parental lines. Acquired resistance to BZM remained stable over months but gradually decreased with extended passages in the absence of BZM, suggesting adaptive changes rather than a single gene mutation as the basis of BZM resistance. BR cells exhibited higher proteasome activity, which was dose-dependently inhibited by higher concentrations of BZM. However, BR cells were able to survive with lower proteasome activity than the parental cells, indicating that BR cells had acquired additional changes. To investigate these changes, we use gene expression profiling (GEP) on Affymetrix U133A plus 2 arrays to compared HBL2-BR (in triplicate) and JEKO-BR (in duplicate) subclones to the corresponding parental lines. Unexpectedly, Gene Set Enrichment Analysis (GSEA) of microarray data revealed reduced expression of the mature B-cell gene signature (including genes for CD19, BLNK, SPIB, SYK) and increased expression of plasma cell differentiation signatures (including genes for CD38, IRF4, BLIMP, CD138) in both HBL-2 BR and JEKO-BR. BR lines also expressed higher protein levels of the master plasma cell regulators BLIMP and IRF4, but did not show enhanced expression of the secretory program controlled by XBP1. Flow cytometry analysis confirmed that BR cells had dramatically reduced expression of B-cell surface markers, including CD19, CD24 and CD52, and expressed plasma cell markers, such as CD38 and CD138. Consistent with a partial plasmacytoid phenotype, BR cells tended to be somewhat larger and more granular than parental cells. Loss of BZM resistance over months of culture in the absence of BZM was paralleled by the recovery of CD19 and CD24 expression and down-regulation of CD38, supporting a mechanistic link between the acquisition of a plasmacytoid phenotype and BZM resistance. We have previously shown that the MCL cell lines Mino and REC-1 are less sensitive to BZM than HBL-2, JEKO and most other MCL cell lines. Here we found that these constitutively resistant cells also showed plasmacytoid features including CD38 and CD138 surface expression, increased granularity and size, and an enlarged endoplasmic reticulum (ER). Combined these changes may enhance the ability of the cells to deal with an increased protein load due to bortezomib inhibition. In addition, we also observed higher expression of IRF4 and its target genes in the constitutively resistant cells, as well as higher IRF4 and CD38 expression in primary tumor cells of patients with poor response to BZM. Given the important role of IRF4 as a survival factor in multiple myeloma, we tested whether BZM treatment could decrease IRF4 expression in MCL cells. Indeed, within 24 hours BZM dose-dependently decreased IRF4 expression and the degree of downregulation of IRF4 correlated with the induction of apoptosis. Knockdown of IRF4 expression by shRNA has been shown to be toxic to myeloma cells (Shaffer et al, Nature 2008). Surprisingly, we found a similar toxic effect of IRF4 knockdown using the same inducible shRNA system in the MCL cell lines HBL2, JEKO and REC, which was more prominent in the latter BZM resistant cell line. These results identify loss of IRF4 expression as an additional mechanism by which BZM may induce cell death. However, overexpression of IRF4 in MCL cells is not sufficient to induce bortezomib resistance, indicating that several components of the plasma cell program cooperate to protect cells from BZM induced apoptosis. Furthermore, we have identified markers of BZM resistance that may be clinically relevant predictors of outcome. Disclosures: No relevant conflicts of interest to declare.

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4481-4481
Yang Han ◽  
Xin Zhang ◽  
Yu Nie ◽  
Yujie Jiang ◽  
Xiaohui Sui ◽  

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.

Blood ◽  
2010 ◽  
Vol 116 (22) ◽  
pp. 4532-4541 ◽  
Michael Hudecek ◽  
Thomas M. Schmitt ◽  
Sivasubramanian Baskar ◽  
Maria Teresa Lupo-Stanghellini ◽  
Tetsuya Nishida ◽  

Monoclonal antibodies and T cells modified to express chimeric antigen receptors specific for B-cell lineage surface molecules such as CD20 exert antitumor activity in B-cell malignancies, but deplete normal B cells. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) was identified as a highly expressed gene in B-cell chronic lymphocytic leukemia (B-CLL), but not normal B cells, suggesting it may serve as a tumor-specific target for therapy. We analyzed ROR1-expression in normal nonhematopoietic and hematopoietic cells including B-cell precursors, and in hematopoietic malignancies. ROR1 has characteristics of an oncofetal gene and is expressed in undifferentiated embryonic stem cells, B-CLL and mantle cell lymphoma, but not in major adult tissues apart from low levels in adipose tissue and at an early stage of B-cell development. We constructed a ROR1-specific chimeric antigen receptor that when expressed in T cells from healthy donors or CLL patients conferred specific recognition of primary B-CLL and mantle cell lymphoma, including rare drug effluxing chemotherapy resistant tumor cells that have been implicated in maintaining the malignancy, but not mature normal B cells. T-cell therapies targeting ROR1 may be effective in B-CLL and other ROR1-positive tumors. However, the expression of ROR1 on some normal tissues suggests the potential for toxi-city to subsets of normal cells.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19566-e19566
Apoorva Jayarangaiah ◽  
Shuai Wang ◽  
Tarek N. Elrafei ◽  
Lewis Steinberg ◽  
Abhishek Kumar

e19566 Background: Limited stage mantle cell lymphoma (MCL) (stage I-II) is rare and occurs in 5-15% of patients. The ideal treatment approach among radiation (RT), chemotherapy (CT), chemoradiotherapy (CRT) or close monitoring (NT) has not been defined. Methods: A retrospective analysis of SEER database (1975 to 2018) was conducted for patients with stage I-II MCL to compare overall survival (OS) among the various treatment modalities in patients >18 years. We excluded patients lacking information on demographic characteristics and survival. Patients were analyzed in 4 groups; RT only, CT only, CRT and no treatment groups. ANOVA test and Chi-square test were used to evaluate parametric and non-parametric variables between groups, respectively. Cancer specific survival (CSS) and OS were assessed by Kaplan-Meier. SPSS 26.0 was used for data analysis. Results: There were in total 2266 patients with limited stage MCL. Median age was 71 years (61-78.25) and predominantly male (65.7%). Stage I MCL was noted in 55.6% and stage II in 44.4% of the patients. The number of patients in each group; RT only, CT only, CRT and NT along with the OS are presented in Table. CSS among these four groups showed no statistically significant differences (p <0.26). OS showed that CT only group has worse survival compared to RT only and CRT groups (p <0.001). CRT has no significant difference in survival compared to RT only (p<0.001). NT was associated with poorest survival rates (p<0.001). Conclusions: In limited stage MCL, RT only and CRT resulted in superior OS compared to CT only. Results suggest a role for incorporation of RT in treatment regimens. One limitation of the study is that the SEER database lacks the ability to distinguish between no receipt of therapy versus lack of availability of data.[Table: see text]

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