Identification of super enhancer-associated key genes for prognosis of germinal center B-cell type diffuse large B-cell lymphoma by integrated analysis

Xi Li,Yuxia Hao,Yan Duan

doi:10.1186/s12920-021-00916-z

Abstract

BackgroundThe pathogenesis of germinal center B-cell type diffuse large B-cell lymphoma (GCB-DLBCL) is not fully elucidated. This study aims to explore the regulation of super enhancers (SEs) on GCB-DLBCL by identifying specific SE-target gene.MethodsWeighted gene co-expression network analysis (WGCNA) was used to screen modules associated with GCB subtype. Functional analysis was performed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. H3K27ac peaks were used to identify SEs. Overall survival analysis was performed using Kaplan–Meier curve with log-rank and Breslow test. The effect of ADNP, ANKRD28 and RTN4IP1 knockdown on Karpas 422 and SUDHL-4 cells proliferation was analyzed by CCK-8. Karpas 422 and SUDHL-4 cells were treated with bromodomain and extra-terminal domain (BET) inhibitor JQ1, and the expression of ADNP, ANKRD28 and RTN4IP1was measured by qRT-PCR.ResultsA total of 26 modules were screened in DLBCL. Turquoise module was closely related to GCB-DLBCL, and its eigengenes were mainly related to autophagy. There were 971 SEs in Karpas 422 cell and 1088 SEs in SUDHL-4 cell. Function of the nearest genes of overall SEs were related to cancer. Six SE-related genes associated with GCB-DLBCL were identified as prognostic markers. Knockdown of ADNP, ANKRD28 and RTN4IP1 inhibited the proliferation of Karpas 422 and SUDHL-4 cells. JQ1 treatment suppressed ADNP, ANKRD28 and RTN4IP1 expression in Karpas 422 and SUDHL-4 cells.ConclusionsA total of 6 SE-related genes associated with GCB-DLBCL overall survival were identified in this study. These results will serve as a theoretical basis for further study of gene regulation and function of GCB-DLBCL.

Highlights

The pathogenesis of germinal center B-cell type diffuse large B-cell lymphoma (GCB-Diffuse large B cell lymphoma (DLBCL)) is not fully elucidated
There was no super enhancer at ADNP, ANKRD28 and RTN4IP1 locus in GM12878 cell (Fig. 8). These results suggested that ADNP, ANKRD28 and RTN4IP1 in GCBDLBCL cell were regulated by super enhancers (SEs), and these SEs were cancer-associated
Consistent with previous studies, other biological pathways, including “T cell receptor signaling pathway” and “MAPK signaling pathway”, were highly altered [25, 26]. These results indicated that the aberrant expression of genes in turquoise module might lead to the disruption of core cancer-signaling pathways, and contribute to carcinogenesis and progression of GCB-DLBCL

Summary

Introduction

The pathogenesis of germinal center B-cell type diffuse large B-cell lymphoma (GCB-DLBCL) is not fully elucidated. This study aims to explore the regulation of super enhancers (SEs) on GCB-DLBCL by identifying specific SE-target gene. DLBCL has obvious heterogeneity and invasiveness, mainly divided into germinal center B-cell type (GCB), activated B-cell type (ABC) and unclassified type (UNC) [1, 2]. One of the important challenges in GCB-DLBCL treatment is the low detection rate in the early stage, which limits the choice of clinical treatment method and leads to poor prognosis [4]. Genetic abnormalities and biological changes are important starting factors for the occurrence and evolution of GCB-DLBCL [5]. Exploring new molecular markers is important for the early diagnosis and treatment of GCB-DLBCL

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