Identification of ADGRE5 as discriminating MYC target between Burkitt lymphoma and diffuse large B-cell lymphoma

Abstract

Background MYC is a heterogeneously expressed transcription factor that plays a multifunctional role in many biological processes such as cell proliferation and differentiation. It is also associated with many types of cancer including the malignant lymphomas. There are two types of aggressive B-cell lymphoma, namely Burkitt lymphoma (BL) and a subgroup of diffuse large cell lymphoma (DLBCL), which both carry MYC translocations and overexpress MYC but both differ significantly in their clinical outcome. In DLBCL, MYC translocations are associated with an aggressive behavior and poor outcome, whereas MYC-positive BL show a superior outcome. Methods To shed light on this phenomenon, we investigated the different modes of actions of MYC in aggressive B-cell lymphoma cell lines subdivided into three groups: (i) MYC-positive BL, (ii) DLBCL with MYC translocation (DLBCLpos) and (iii) DLBCL without MYC translocation (DLBCLneg) for control. In order to identify genome-wide MYC-DNA binding sites a chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) was performed. In addition, ChIP-Seq for H3K4me3 was used for determination of genomic regions accessible for transcriptional activity. These data were supplemented with gene expression data derived from RNA-Seq. Results Bioinformatics integration of all data sets revealed different MYC-binding patterns and transcriptional profiles in MYC-positive BL and DLBCL cell lines indicating different functional roles of MYC for gene regulation in aggressive B-cell lymphomas. Based on this multi-omics analysis we identified ADGRE5 (alias CD97 ) - a member of the EGF-TM7 subfamily of adhesion G protein-coupled receptors - as a MYC target gene, which is specifically expressed in BL but not in DLBCL regardless of MYC translocation. Conclusion Our study describes a diverse genome-wide MYC-DNA binding pattern in BL and DLBCL cell lines with and without MYC translocations. Furthermore, we identified ADREG5 as a MYC target gene able to discriminate between BL and DLBCL irrespectively of the presence of MYC breaks in DLBCL. Since ADGRE5 plays an important role in tumor cell formation, metastasis and invasion, it might also be instrumental to better understand the different pathobiology of BL and DLBCL and help to explain discrepant clinical characteristics of BL and DLBCL. Electronic supplementary material The online version of this article (10.1186/s12885-019-5537-0) contains supplementary material, which is available to authorized users.

Long Non-coding RNA MIAT Knockdown Prevents the Formation of Intracranial Aneurysm by Downregulating ENC1 via MYC

“…The subsequent finding in the current study was that MIAT increased the expression of ENC1 by promoting the ability of MYC binding to the promoter region of ENC1. Myelocytomatosis oncogene is a TF that plays multiple functions in several biological processes like proliferation and differentiation and is associated with various cancers such as lymphomas and breast cancer ( Kleo et al, 2019 ; Lourenco et al, 2019 ). Similarly, another study documented that the transcriptional activity of MYC can be maintained by lncRNA MYMLR ( Kajino et al, 2019 ).…”

Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition

“…We also wanted to assess the response of human B-cell lymphoma cell lines to M-100 in different BL and DLBCL cell lines. All used cell lines are characterized by MYC translocations or amplifications (26)(27)(28)(29)(30)(31) but the individual MYC mutation profile differs heavily (Figure 3A). M-100 treatment resulted in a dose-dependent induction of apoptosis in human BL cell lines Ramos and Raji as demonstrated by the accumulation of Annexin V + cells (Figure 3B).…”

Opportunities and challenges for drug discovery in modulating Adhesion G protein-coupled receptor (GPCR) functions

“…was recently identified as an MYC target gene that is specifically expressed in Burkitt lymphoma cells [143].…”