NOTCH1 promotes the elevation of GM-CSF and IL-6 through the EZH2/STAT3 pathway to facilitate the fibrotic state of the myocardium in DLBCL.

in PloS one by Huimin Zhang, Wen Dong, Lihong Zhang, Bing Ma, Jianying Wang, Yang Shen, Dan Zhao, Wanyi Yin, Yuexian Li, Qingchi Liu

TLDR

  • The study found that NOTCH1 signaling pathway plays a critical role in DLBCL-related heart pathogenesis, and inhibiting NOTCH1 may be a promising therapeutic strategy for managing heart disease in DLBCL patients.

Abstract

Investigate the role of the Neurogenic locus notch homolog protein 1 (NOTCH1) signaling pathway in Diffuse large B-cell lymphoma (DLBCL)-related heart pathogenesis. Utilize R (version 4.2.1) to retrieve DLBCL and myocardial infarction datasets from the GEO database, normalize data with limma, perform differential analysis and GO analysis with GOplot, and visualize findings with ggplot2. Various assays were conducted including stable cell line construction, myocardial infarction modeling, imaging, Western Blot, ELISA, staining, and functional assays. Significant gene expression and pathway disparities were found between DLBCL and myocardial infarction samples. NOTCH1, The molecules named Recosomal-binding protein 70 (RBP-J), zeste 2 polycomb repressive complex 2 subunit (EZH2), trimethylated histone H3 at lysine 27 (H3K27me3), Signal Transducer And Activator Of Transcription 3 (STAT3) and Jumonji domain containing-3 (JMJD3) matters a lot in DLBCL. NOTCH1 inhibition decreased DLBCL cell proliferation and activity, reduced inflammatory factors, and improved myocardial fibrosis and infarction severity. NOTCH1 inhibits Granulocyte-macrophage colony-stimulating factor (GM-CSF) and Interleukin-6 (IL-6) expressions depending on STAT3 and EZH2. Co-culturing with DLBCL cells increased fibroblast proliferation, invasion, and fibrosis. NOTCH1 signaling influences DLBCL development and myocardial infarction severity through the EZH2/STAT3 pathway, leading to increased heart fibrosis.

Overview

  • The study investigated the role of the NOTCH1 signaling pathway in Diffuse large B-cell lymphoma (DLBCL)-related heart pathogenesis.
  • The researchers used R to retrieve datasets from the GEO database, normalize data with limma, and perform differential analysis and GO analysis with GOplot and ggplot2.
  • The study aimed to elucidate the molecular mechanisms underlying DLBCL-associated heart disease and identify potential therapeutic targets.

Comparative Analysis & Findings

  • Significant gene expression and pathway disparities were found between DLBCL and myocardial infarction samples, with NOTCH1 signaling pathway being a key player.
  • NOTCH1 inhibition decreased DLBCL cell proliferation and activity, reduced inflammatory factors, and improved myocardial fibrosis and infarction severity.
  • The study identified key molecules involved in DLBCL, including RBP-J, EZH2, H3K27me3, STAT3, and JMJD3, which interact with NOTCH1 and influence disease progression.

Implications and Future Directions

  • The findings suggest that NOTCH1 signaling plays a crucial role in DLBCL development and myocardial infarction severity, highlighting its potential as a therapeutic target.
  • Future studies should investigate the mechanisms by which NOTCH1 inhibition modulates fibrosis and inflammation in DLBCL.
  • The study's findings provide new insights into the complex interactions between DLBCL and the heart, which may lead to novel therapeutic strategies for heart disease management in DLBCL patients.
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