Dataset Information

Clinicopathological spectrum of Diffuse Large B Cell lymphoma: a study targeting population yet unexplored in Pakistan.

ABSTRACT:

Objective

Diffuse Large B Cell Lymphoma (DLBCL) is the most common type of Non-Hodgkin Lymphoma (NHL). The aim of this study was to assess the clinico pathological characteristics of DLBCL specifically, among the affected individuals residing in Northern areas of Pakistan who had not been previously included in major lymphoma studies due to their remote location.

Results

Mean age of the patients was 49.7 years. Male: female ratio was 1.5:1. Primary site was lymph node in 99 (71.74%) patients, out of which, 36 (26.09%) patients had B symptoms and 19 (13.77%) patients had stage IV disease. 39 (28.26%) patients had primary extra nodal involvement, 4 (2.90%) patients had B symptoms and 3 (2.17%) had stage IV disease. Extra nodal sites involved in primary extra nodal DLBCL were gastrointestinal tract (GIT) 19 (48.72%), tonsils 6 (15.38%), spine 4 (10.26%), soft tissue swelling 3 (7.69%), parotid gland 2 (5.13%), thyroid 2 (5.13%) central nervous system (CNS) 1 (2.56), breast 1 (2.56%) and bone marrow 1 (2.56%). Our study revealed increased percentage of patients with nodal DLBCL in stage IV and with B symptoms. Few patients with primary extra nodal DLBCL had B symptoms and stage IV disease at presentation. GIT was the most common site of involvement in primary extra nodal DLBCL.

SUBMITTER: Mahmood H

PROVIDER: S-EPMC8434720 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Histone deacetylases (HDACs) are involved in tumorigenesis and progression, however, their role in diffuse large B-cell lymphoma (DLBCL) is not well understood. In this study, we examined the expression levels, mutations, and clinical significance of HDACs in DLBCL. Additionally, we investigated the therapeutic potential of Chidamide, a novel HDAC inhibitor, to provide scientific evidence for targeting HDACs in DLBCL patients. We extracted transcriptome data of DLBCLs--including 47 lymph node samples and 337 whole-blood-cell controls--from The Cancer Genome Atlas. Bioinformatic analyses of HDAC expression, mutation, and correlation with the clinical significance of DLBCL patients were performed with the Gene Expression Profiling Interactive Analysis, GENEMANIA, and web-based software including cBioPortal and WebGestalt. To examine the therapeutic effect of Chidamide, DLBCL cell lines (WSU-DLCL-2 and DB cells) were employed. Cell proliferation and apoptosis were analyzed with Cell Counting Kit-8 and flow cytometry assays. The impact of Chidamide treatment was also analyzed by RNA sequencing of treated DB cells. Western blot was used to explore the molecular mechanism of the cytotoxicity of Chidamide on DLBCL cell lines. The expression of some HDACs (HDAC1, 2, 3, 4, 6, 7, 8, and 9) were significantly higher in the lymph node samples of DLBCL than that in whole-blood-cell controls. Moreover, we found that the mutation rate of HDACs was also higher in DLBCL tissues, although the overall survival of DLBCL patients was not associated with HDAC expression. Chidamide was found to have a cytotoxic effect on DLBCL cells in a dose-dependent manner, while transcriptome analysis and western blot revealed that using it for treatment impacted several biological processes, including PI3K/AKT signaling, mTOR signaling, the cell cycle, and apoptosis pathways. Alterations of HDAC genes, including enhanced expression and mutations, are positively related to DLBCL. Targeting HDACs with specific inhibitors such as Chidamide may represent a potential therapeutic approach for DLBCL patients.

Project description:BackgroundDiffuse large B-cell lymphoma (DLBCL) is a heterogeneous malignant lymphoma with distinct characteristics. Patients with treatment failure after the standard immunochemotherapy have worse prognosis, which implies the necessity to uncover novel targets. The C-X-C chemokine receptor 4 (CXCR4) overexpression has been identified in several hematopoietic malignancies. However, the expression signatures and prognostic significance of CXCR4 in DLBCL associated with clinicopathological features remain unclear.MethodsGene expression profiles of DLBCL were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Then, a meta-analysis with an integrated bioinformatic analysis was performed to assess the relationship between CXCR4 expression and clinicopathological features of DLBCL. Finally, experimental verification including immunohistochemical (IHC) staining and real-time quantitative PCR (qPCR) was carried out using patient samples. In vitro cell line viability tests were conducted using CXCR4 inhibitor WZ811.ResultsDLBCL patients with activated B-cell-like (ABC) subtype have higher expression level of CXCR4 with worse survival. Differential expressed genes in the CXCR4-upregulation group were enriched in canonical pathways associated with oncogenesis. DLBCL with CXCR4 upregulation had lower degree of CD8+ T cell infiltration. TIMER analysis demonstrated that the CXCR4 expression was positively correlated with the expression of CD5, MYC, NOTCH1, PDCD1, CD274, mTOR, FOXO1, and hnRNPA2B1 in DLBCL. IHC study in patient samples showed the positive correlation between CXCR4 and nongerminal center B-cell (non-GCB) subtype and mTOR expression. Meanwhile, quantitative polymerase chain reaction results revealed that high CXCR4 mRNA level was correlated to double-hit DLBCL. Finally, cell viability test showed that WZ811 exerted antiproliferation effect in DLBCL cell lines in a dose-dependent manner.ConclusionCXCR4 was upregulated in ABC-DLBCL associated with worse prognosis. Our analysis predicted CXCR4 as a potential target for DLBCL treatment, which may serve as an inhibitor both on BCR signaling and nuclear export warranting further investigation in clinical trials.

Dataset Information

Clinicopathological spectrum of Diffuse Large B Cell lymphoma: a study targeting population yet unexplored in Pakistan.

Objective

Results

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