Expression of <scp>ELF</scp>1, a lymphoid <scp>ETS</scp> domain‐containing transcription factor, is recurrently lost in classical Hodgkin lymphoma

Paczkowska, Julia; Soloch, Natalia; Bodnar, Magdalena; Kiwerska, Katarzyna; Janiszewska, Joanna; Vogt, J.; Domanowska, Ewa; Martín‐Subero, José I.; Ammerpohl, Ole; Klapper, Wolfram; Marszałek, Andrzej; Siebert, Reiner; Giefing, Maciej

doi:10.1111/bjh.15757

Cited by 11 publications

(9 citation statements)

References 44 publications

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“…49 Both transcription factors have also been indicated to be required for normal B cell development. 50,51 Furthermore, the EICE is a well-known binding motif for IRF8-PU.1, as well as IRF4-PU.1 complexes. 18,35,36 The expression of IRF4 is, like IRF8, restricted to hematopoietic cells and also implicated in the development of dendritic cells and B cells.…”

Section: Discussionmentioning

confidence: 99%

IRF8 is a transcriptional activator of CD37 expression in diffuse large B-cell lymphoma

et al. 2022

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Diffuse large B-cell lymphoma (DLBCL) represents the most common form of non-Hodgkin lymphoma that is still incurable in a large fraction of patients. Tetraspanin CD37 is highly expressed on mature B lymphocytes and multiple CD37-targeting therapies are under clinical development for non-Hodgkin lymphoma. However, CD37 expression is non-detectable in ~50% of DLBCL patients which correlates with inferior treatment outcome, but the underlying mechanisms for differential CD37 expression in DLBCL are still unknown. Here, we investigated the regulation of the CD37 gene in human DLBCL at the (epi-)genetic and transcriptional level. No differences were observed in DNA methylation within the CD37 promoter region between CD37-positive and CD37-negative primary DLBCL patient samples. On the contrary, CD37-negative DLBCL cells specifically lacked CD37 promoter activity, suggesting differential regulation of CD37 gene expression. Using an unbiased quantitative proteomic approach, we identified transcription factor IRF8 to be significantly higher expressed in nuclear extracts of CD37-positive as compared to CD37-negative DLBCL. Direct binding of IRF8 to the CD37 promoter region was confirmed by DNA pull-down assay combined with mass spectrometry, and targeted chromatin immunoprecipitation. Functional analysis indicated that IRF8 overexpression enhanced CD37 protein expression, while CRISPR/Cas9 knock-out of IRF8 decreased CD37 levels in DLBCL cell lines. Immunohistochemical analysis in a large cohort of primary DLBCL (n=206) revealed a significant correlation of IRF8 expression with detectable CD37 levels. Together, this study provides new insight into the molecular mechanisms underlying differential CD37 expression in human DLBCL, and reveals IRF8 as transcriptional regulator of CD37 in B-cell lymphoma.

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Section: Discussionmentioning

confidence: 99%

IRF8 is a transcriptional activator of CD37 expression in diffuse large B-cell lymphoma

et al. 2022

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“…GATA3, FOXP3 and EOMES), and members of ETS family (e.g. EBF1, ELF1, ETV6), [4][5][6] were down-regulated and might contribute to the differentiation defect of PDX and RLH cells (Figure 2B, group 3 and 4 TFs). These results were consistent with gene ontology analysis using all differentially expressed genes (DEGs) (PDX vs. normal cells, or RLH vs. normal cells), which indicated that DEGs enriched in PDX tumours were strongly associated with MAPK pathway that utilizes AP-1 families of TFs for signal transduction 7 (Figure 2C).…”

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confidence: 99%

Integrative genome‐wide chromatin accessibility and transcriptome profiling of diffuse large B‐cell lymphoma

Fang

Zhang

et al. 2022

Clinical & Translational Med

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Dear Editor,Diffuse large B-cell lymphoma (DLBCL) represents the most common neoplastic disorder of B-lymphocytes with significant clinicopathological, immunophenotypic and molecular heterogeneity. 1 Aiming to investigate the epigenomic and transcriptomic signatures as well as the underlying pathogenetic mechanism and therapeutic rationale of DLBCL, we performed assay for transposaseaccessible chromatin using sequencing (ATAC-seq) on 10 DLBCL patient-derived xenograft (PDX) models and identified 93 221 reproducible accessible peaks per PDX (Figures S1-S4). In an unsupervised clustering analysis with previously published ATAC-seq data on major haematological cell types, 2,3 all PDX tumours clustered together and, as expected, their closest normal cell types were cells of the B lymphocyte lineage, including naïve B (CD19 pos CD27 neg ), memory B (CD19 pos CD27 pos ), plasmablast (CD19 pos CD27 pos CD138 pos CD20 neg ) and common lymphoid progenitors (CLP, Lin neg CD34 pos CD38 pos CD10 pos CD45RA pos ) (Figures 1A and S5a). Using the chromatin accessibility profiles of normal B cells for comparison, we identified a set of differentially accessible regions (DARs, Wald test, p adj < .01 by pair-wise comparison) specifically active in PDX tumours (Figure 1B, cluster 1; Figure S5b). The PDX-specific DARs were significantly associated with leukocyte activation, cytokine-mediated signalling, I-kappa-B/NF-kappa-B (NF-κB) signalling and MAP kinase activity according to GREAT analysis (see the Supporting Information section) (Figure 1C). Moreover, chromVAR analysis (see the Supporting Information section) of the ATAC-seq data revealed a group of transcription factor (TF)-binding motifs highly enriched in PDX tumours, including the binding sequence motifs for AP-1 family, NF-κB family and POU family (Figure 1D-F).Next, to explore the trans-acting factors activated in DLBCL, we performed RNA-sequencing (RNA-seq) on PDX samples (n = 19, 9/10 PDXs had replicates) and compared them with RNA-seq data set of CLP, naïve B, This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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“…More specifically, PU.1 has a proven role in the regulation of Igκ transcription and rearrangement, as does ELF1 in the activation of several B-cell specific tyrosine kinases in mice that are important for proper BCR signaling [34,35]. Both factors are recurrently attenuated in cHL [5,16]. However, TNFAIP3 is a ubiquitin-modifying enzyme that targets the RIP1 protein for degradation.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, these putatively upregulated genes also seem to be involved to some extent in the regulation of transcription (Table 1). In light of these results, we further focused on deregulated miRNAs and their putative interactions with B-cell specific transcription factors SPI1 and ELF-1 attenuated in cHL [5,16] and also the NF-kB inhibitor TNFAIP3 recurrently inactivated in this lymphoma [17]. We selected the putative hsa-miR-27a-5p:SPI1, hsa-miR-330-3p:ELF-1 (two miRNA binding sites were tested), hsa-miR-542-3p:ELF1, hsa-miR-450b-5p:ELF-1 and the hsa-miR-23a-3p:TNFAIP3 interactions for experimental testing (Table 2).…”

Section: Biological Processes Deregulated By Mirnas In Chlmentioning

confidence: 99%

“…The canonical mechanism through which epigenetic alterations contribute to neoplastic disease is the hypermethylation of the promoter regions of tumor suppressor genes (TSGs), leading to their transcriptional silencing or the activation of oncogenes by loss of DNA methylation. However, in cHL, in addition to the usual hypermethylation of TSG promoters, DNA hypermethylation was reported to contribute to the loss-of-B-cell phenotype of HRS cells by silencing the B-cell specific transcription factors [4,5]. In this context, most studies focus exclusively on DNA methylation; in contrast, the role of the other epigenetic mechanism, namely miRNA in the regulation of B-cell specific transcription factors in the pathogenesis of cHL has remained largely understudied.…”

Section: Introductionmentioning

confidence: 99%

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Deregulated miRNAs Contribute to Silencing of B-Cell Specific Transcription Factors and Activation of NF-κB in Classical Hodgkin Lymphoma

Paczkowska

Janiszewska

Ustaszewski

et al. 2021

Cancers

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A hallmark of classical Hodgkin lymphoma (cHL) is the attenuation of B-cell transcription factors leading to global transcriptional reprogramming. The role of miRNAs (microRNAs) involved in this process is poorly studied. Therefore, we performed global miRNA expression profiling using RNA-seq on commonly used cHL cell lines, non-Hodgkin lymphoma cell lines and sorted normal CD77+ germinal centre B-cells as controls and characterized the cHL miRNome (microRNome). Among the 298 miRNAs expressed in cHL, 56 were significantly overexpressed and 23 downregulated (p < 0.05) compared to the controls. Moreover, we identified five miRNAs (hsa-miR-9-5p, hsa-miR-24-3p, hsa-miR-196a-5p, hsa-miR-21-5p, hsa-miR-155-5p) as especially important in the pathogenesis of this lymphoma. Target genes of the overexpressed miRNAs in cHL were significantly enriched (p < 0.05) in gene ontologies related to transcription factor activity. Therefore, we further focused on selected interactions with the SPI1 and ELF1 transcription factors attenuated in cHL and the NF-ĸB inhibitor TNFAIP3. We confirmed the interactions between hsa-miR-27a-5p:SPI1, hsa-miR-330-3p:ELF-1, hsa-miR-450b-5p:ELF-1 and hsa-miR-23a-3p:TNFAIP3, which suggest that overexpression of these miRNAs contributes to silencing of the respective genes. Moreover, by analyzing microdissected HRS cells, we demonstrated that these miRNAs are also overexpressed in primary tumor cells. Therefore, these miRNAs play a role in silencing the B-cell phenotype in cHL.

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Expression of ELF1, a lymphoid ETS domain‐containing transcription factor, is recurrently lost in classical Hodgkin lymphoma

Cited by 11 publications

References 44 publications

IRF8 is a transcriptional activator of CD37 expression in diffuse large B-cell lymphoma

IRF8 is a transcriptional activator of CD37 expression in diffuse large B-cell lymphoma

Integrative genome‐wide chromatin accessibility and transcriptome profiling of diffuse large B‐cell lymphoma

Deregulated miRNAs Contribute to Silencing of B-Cell Specific Transcription Factors and Activation of NF-κB in Classical Hodgkin Lymphoma

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