MEF2B is a member of the BCL6 gene transcriptional complex and induces its expression in diffuse large B-cell lymphoma of the germinal center B-cell-like type

Jamal, Siraj M. El; Grada, Zakaria; Dinali, Mohamed H El; Zhou, He; Hassan, Sofie-Yasmin; Saad, Ali G.; Gibson, Bradley; Zhou, Xinchun; Abulsayen, Hend A; Khadra, Helmi; Friedman, Jessica; Shalaby, Hosam; Kadi, Abida; Megahed, Mosaad; Emberesh, Myesa; Teruya‐Feldstein, Julie; Firpo-Betancourt, Adolfo; Haïkel, Youssef; Fraig, Mostafa; Hassan, Mohamed

doi:10.1038/s41374-018-0152-2

Cited by 10 publications

(8 citation statements)

References 40 publications

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“…19 The expression of MEF2B protein is important for the growth of GCB-DLBCL cells and is an essential component of the BCL6 gene transcriptional complex for the regulation of DLBCL growth. 20 In this study, we performed NGS in patients with both ctDNA and tissue biopsy. Mutations were detected in ctDNA with 87.5% sensitivity in comparison with gDNA derived from tumor biopsy, which was consistent with previous reports.…”

Section: Discussionmentioning

confidence: 99%

<p>Genotyping on ctDNA Identifies Shifts in Mutation Spectrum Between Newly Diagnosed and Relapse/Refractory DLBCL</p>

Liu¹,

Yang²,

Zhao³

et al. 2020

OTT

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Purpose Diffuse large B cell lymphoma (DLBCL) is an aggressive B-cell malignancy with clinical and molecular heterogeneity whose genetics may have clinical implications for patient stratification and treatment. The circulating tumor DNA (ctDNA) is a novel noninvasive, real-time, and tumor-specific biomarker harboring tumor-derived genetic alterations that are identical to those of tumor cells, thus showing great promise in individualized medicine, including precise diagnosis, prediction of prognosis, response monitoring, and relapse detection for DLBCL. Patients and Methods In this study, we applied NGS analysis to tumor biopsies and ctDNA samples from 16 DLBCL subjects. Then, we compared the genomic alterations from 41 newly diagnosed patients and 56 relapsed/refractory (R/R) patients. Results Our results show that ctDNA can function as a liquid biopsy for tracking recurrently mutated genes in DLBCL (sensitivity: 87.50%). The mutational profiles of newly diagnosed and R/R DLBCL groups largely overlapped, but the frequencies of some gene mutations differ between the two cohorts. The distribution of mutations also revealed different frequencies in the two cohorts due to different signaling pathways. Genes from apoptosis pathway, immune response and BCR pathway suffered more mutations in R/R patients. Conclusion Overall, this study establishes ctDNA as an easily accessible source of tumor DNA for DLBCL genotyping and provides a deeper understanding of the somatic alteration spectrum for both newly diagnosed and R/R DLBCL patients.

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Section: Discussionmentioning

confidence: 99%

<p>Genotyping on ctDNA Identifies Shifts in Mutation Spectrum Between Newly Diagnosed and Relapse/Refractory DLBCL</p>

Liu¹,

Yang²,

Zhao³

et al. 2020

OTT

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“…Interestingly, using this criterion, the CD19 + CD138 + B cell gene set had higher levels of expression of Cd9 and Cd44 , two genes which are associated with adhesion [37, 38]. Mef2b , a member of the Bcl6 complex [39] was induced to a greater extent in the CD19 + CD138 - subset. Other genes with the same pattern as Mef2b included Pim1 and Asns , involved in cell cycle and survival [40, 41].…”

Section: Resultsmentioning

confidence: 99%

Gene expression profiling reveals B cells are highly educated by the pancreatic environment during autoimmune diabetes

Boldison

Hopkinson

Davies

et al. 2022

Preprint

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B cells play an important role in driving the development of type 1 diabetes, however, it remains unclear how they contribute to local beta-cell destruction during disease progression. Using gene expression profiling of B cell subsets in the pancreas and pancreatic lymph nodes, we reveal that B cells are highly modified by the inflamed pancreatic tissue and can be distinguished by their transcriptional profile from those in the lymph node. We identified both a discrete and a core shared gene expression profile in islet CD19+CD138- and CD19+CD138+ B cell subsets, the latter known to have enriched autoreactivity during diabetes development. Upon localisation to pancreatic islets, CD138+ B cells overexpressed genes associated with adhesion molecules and growth factors compared to CD138- B cells. Their shared signature displayed gene expression changes related to the differentiation of antibody-secreting cells and gene regulatory networks associated with interferon signalling pathways, pro-inflammatory cytokines and toll-like receptor activation. Finally, abundant TLR7 expression was detected in islet B cells, and was enhanced specifically in CD138+ B cells. Our study, therefore, provides a detailed transcriptional analysis of islet B cells identifying specific gene signatures and interaction networks that point towards a functional role for B cells in driving autoimmune diabetes.

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“…Reanalyses of ChIP-Seq data available in the various public domains revealed co-occupancy of EBNA2 with B-cell master regulatory factors - RBP- Jκ and EBF1 along with several other B-cell specific transcription factors including MEF2B, IKZF1, EP300 and SPI1 onto the distal CA9 promoter/enhancer region. In support of this, increased MEF2B expression was shown to be associated with several B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL), a frequently EBV infected B-cell neoplasm [83]. In addition, EBNA1 transcriptionally activates EBF1 and MEF2B expressions, which play an important role for enhanced survival of EBV latently infected cells [80].…”

Section: Discussionmentioning

confidence: 99%

Differential Carbonic Anhydrase Activities Control EBV-Induced B-Cell Transformation and Lytic Cycle Reactivation

Malik,

Biswas,

Sarkar

et al. 2023

Preprint

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Epstein-Barr virus (EBV) contributes to ∼1% of all human cancers including several B-cell neoplasms. A characteristic feature of EBV life cycle is its ability to transform metabolically quiescent B-lymphocytes into hyperproliferating B-cell blasts with the establishment of viral latency, while intermittent lytic cycle induction is necessary for the production of progeny virus. Our RNA-Seq analyses of both latently infected naïve B-lymphocytes and transformed B-lymphocytes upon lytic cycle replication indicate a contrasting expression pattern of a membrane-associated carbonic anhydrase isoform CA9, an essential component for maintaining cell acid-base homeostasis. We show that while CA9 expression is transcriptionally activated during latent infection model, lytic cycle replication restrains its expression. Pharmacological inhibition of CA-activity using specific inhibitors retards EBV induced B-cell transformation, inhibits B-cells outgrowth and colony formation ability of transformed B-lymphocytes through lowering the intracellular pH, induction of cell apoptosis and facilitating degradation of CA9 transcripts. Reanalyses of ChIP-Seq data along with utilization of EBNA2 knockout virus and sh-RNA mediated knockdown of CA9 expression we further demonstrate that EBNA2 mediated CA9 transcriptional activation is essential for EBV latently infected B-cell survival. In contrast, during lytic cycle reactivation CA9 expression is transcriptionally suppressed by the key EBV lytic cycle transactivator, BZLF1 through its transactivation domain. Overall, our study highlights the dynamic alterations of CA9 expression and its activity in regulating pH homeostasis act as one of the major drivers for EBV induced B-cell transformation and subsequent B-cell lymphomagenesis.

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MEF2B is a member of the BCL6 gene transcriptional complex and induces its expression in diffuse large B-cell lymphoma of the germinal center B-cell-like type

Cited by 10 publications

References 40 publications

<p>Genotyping on ctDNA Identifies Shifts in Mutation Spectrum Between Newly Diagnosed and Relapse/Refractory DLBCL</p>

<p>Genotyping on ctDNA Identifies Shifts in Mutation Spectrum Between Newly Diagnosed and Relapse/Refractory DLBCL</p>

Gene expression profiling reveals B cells are highly educated by the pancreatic environment during autoimmune diabetes

Differential Carbonic Anhydrase Activities Control EBV-Induced B-Cell Transformation and Lytic Cycle Reactivation

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