IRF4 modulates the response to BCR activation in chronic lymphocytic leukemia regulating IKAROS and SYK

Maffei, Rossana; Fiorcari, Stefania; Benatti, Simone; Atene, Claudio Giacinto; Martinelli, Silvia; Zucchini, Patrizia; Potenza, Leonardo; Luppi, Mario; Marasca, Roberto

doi:10.1038/s41375-021-01178-5

Cited by 16 publications

(12 citation statements)

References 47 publications

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“…As shown in Fig 10A and 10B , over-expression of IRF4 decreased expression of both the NFATc1 and NFATc2 proteins in BJAB and Akata BL lines. Consistent with its previously reported ability to inhibit BCR-mediated signaling [ 41 ], IRF4 expression also decreased the effect of BCR activation on phospho-ERK induction. Together, these results suggest that IRF4 at least partially decreases lytic EBV reactivation by decreasing NFAT activity in B cells, as well as other downstream mediators of BCR signaling.…”

Section: Resultssupporting

confidence: 88%

“…We considered the possibility that decreased IRF4 expression contributes to the lytic phenotype of T2 EBV-infected LCLs since IRF4 (although essential for T1 LCL survival [ 39 , 40 ]) has been shown to inhibit BCR signaling [ 41 ], and decreased IRF4 expression enhances the growth of BCR-dependent chronic lymphocytic leukemia tumors in both humans and mouse models [ 42 – 45 ]. To assess whether the gene expression differences in T2 LCLs versus T1 LCLs could at least partially reflect decreased IRF4 expression in the T2 LCLs, we used GSEA to compare cellular gene expression in our bulk RNA-seq analysis of T2 versus T1 LCLs, with a previously published list of cellular genes upregulated in IRF4 knock-out versus control T1 LCLs [ 39 ].…”

Section: Resultsmentioning

confidence: 99%

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Reduced IRF4 expression promotes lytic phenotype in Type 2 EBV-infected B cells

et al. 2022

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Humans are infected with two types of EBV (Type 1 (T1) and Type 2 (T2)) that differ substantially in their EBNA2 and EBNA 3A/B/C latency proteins and have different phenotypes in B cells. T1 EBV transforms B cells more efficiently than T2 EBV in vitro, and T2 EBV-infected B cells are more lytic. We previously showed that both increased NFATc1/c2 activity, and an NFAT-binding motif within the BZLF1 immediate-early promoter variant (Zp-V3) contained in all T2 strains, contribute to lytic infection in T2 EBV-infected B cells. Here we compare cellular and viral gene expression in early-passage lymphoblastoid cell lines (LCLs) infected with either T1 or T2 EBV strains. Using bulk RNA-seq, we show that T2 LCLs are readily distinguishable from T1 LCLs, with approximately 600 differentially expressed cellular genes. Gene Set Enrichment Analysis (GSEA) suggests that T2 LCLs have increased B-cell receptor (BCR) signaling, NFAT activation, and enhanced expression of epithelial-mesenchymal-transition-associated genes. T2 LCLs also have decreased RNA and protein expression of a cellular gene required for survival of T1 LCLs, IRF4. In addition to its essential role in plasma cell differentiation, IRF4 decreases BCR signaling. Knock-down of IRF4 in a T1 LCL (infected with the Zp-V3-containing Akata strain) induced lytic reactivation whereas over-expression of IRF4 in Burkitt lymphoma cells inhibited both NFATc1 and NFATc2 expression and lytic EBV reactivation. Single-cell RNA-seq confirmed that T2 LCLs have many more lytic cells compared to T1 LCLs and showed that lytically infected cells have both increased NFATc1, and decreased IRF4, compared to latently infected cells. These studies reveal numerous differences in cellular gene expression in B cells infected with T1 versus T2 EBV and suggest that decreased IRF4 contributes to both the latent and lytic phenotypes in cells with T2 EBV.

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Section: Resultssupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Reduced IRF4 expression promotes lytic phenotype in Type 2 EBV-infected B cells

et al. 2022

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“…In detail, we found that all three tumor infiltrating B lymphocytes (TIL-B) subsets, activated or effector memory CD8+ and activated or effector memory CD4+T cells were significantly correlated with IRF4 expression (|r| > 0.3 and P < 0.001) (Figure 4). In fact, several studies showed that IRF4 plays a key role in diverse pathways related immune cell (21)(22)(23)(24)(25). Above all, high IRF4 expression might be reflect a state having predominantly tumor-specific TILs which play an important role in tumor control and prevent tumor progression (26).…”

Section: Discussionmentioning

confidence: 99%

Interferon Regulatory Factor 4 Correlated With Immune Cells Infiltration Could Predict Prognosis for Patients With Lung Adenocarcinoma

Zhai

Zhang

et al. 2021

Front. Oncol.

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BackgroundImmune related interferon regulatory factor 4 (IRF4) is a member of the IRF family, whereas the clinical significance and possible role of IRF4 in lung adenocarcinoma (LUAD) remains unclear. We aimed to investigate the role of IRF4 in predicting the prognosis of LUAD patients.MethodsUsing The Cancer Genome Atlas (TCGA) database and our immunohistochemical (IHC) cohort, we analyzed the correlation between IRF4 expression and clinical characteristics, and the prognostic value of IRF4 was also evaluated in LUAD. The potential biological functions of IRF4 in LUAD were analyzed by Gene Set Enrichment Analysis (GSEA). The relationship between IRF4 and immune cell infiltration were evaluated by TISIDB database and our own IHC cohort. In addition, an immune checkpoint inhibitor (ICI) treated cohort from Gene Expression Omnibus database was used to determine the role of IRF4 in LUAD patients with immunotherapy.ResultsWe found that either mRNA or protein expression level of IRF4 was significantly higher in LUAD than in normal tissues (P < 0.001). The elevate in IRF4 expression in LUAD was significantly associated with the earlier clinical stage (P = 0.002). Patients with LUAD and IRF4 high expression correlated with significant longer overall survival in both TCGA database (P < 0.05) and our IHC-cohort (P = 0.001). Our results also demonstrated that IRF4 could serve as an independent favorable prognostic factor in patients with LUAD. GSEA analysis indicated that high IRF4 expression group enriched with several immune-related pathways, such as B cell receptor signaling pathway, T cell receptor signaling pathway and cytokine-cytokine receptor interaction signaling pathway. In LUAD, IRF4 positively correlated with several different immune infiltrations including various B cells, CD8+ T cells and CD4+ T cells both in mRNA and protein levels. Additionally, we found that the expression of IRF4 was positively associated with PD-1 and PD-L1 mRNA expression levels, and IRF4 high expression predicted moderate better survival in LUAD with immunotherapy (P = 0.071).ConclusionsOur results suggested that IRF4 was associated with higher B cells and T cells infiltration levels and might be a favorable prognostic biomarker in LUAD patients, whereas the potential prognostic role of IRF4 in ICI-treated patients needed further exploration.

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“…Induction of IKAROS in CLL cells is associated with poor disease outcome [79] and promotes BCR signaling [80]. Taking into account that IKAROS tumor suppressive capacity includes an induction of enhancers in T cells [81], the hypomethylation in SF3B1 mut patients at IKAROS binding sites and the enrichment of the hypomethylation sites in weak enhancers is noticeable and requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Altered DNA Methylation Profiles in SF3B1 Mutated CLL Patients

Pacholewska

Grimm

Herling

et al. 2021

IJMS

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Mutations in splicing factor genes have a severe impact on the survival of cancer patients. Splicing factor 3b subunit 1 (SF3B1) is one of the most frequently mutated genes in chronic lymphocytic leukemia (CLL); patients carrying these mutations have a poor prognosis. Since the splicing machinery and the epigenome are closely interconnected, we investigated whether these alterations may affect the epigenomes of CLL patients. While an overall hypomethylation during CLL carcinogenesis has been observed, the interplay between the epigenetic stage of the originating B cells and SF3B1 mutations, and the subsequent effect of the mutations on methylation alterations in CLL, have not been investigated. We profiled the genome-wide DNA methylation patterns of 27 CLL patients with and without SF3B1 mutations and identified local decreases in methylation levels in SF3B1mut CLL patients at 67 genomic regions, mostly in proximity to telomeric regions. These differentially methylated regions (DMRs) were enriched in gene bodies of cancer-related signaling genes, e.g., NOTCH1, HTRA3, and BCL9L. In our study, SF3B1 mutations exclusively emerged in two out of three epigenetic stages of the originating B cells. However, not all the DMRs could be associated with the methylation programming of B cells during development, suggesting that mutations in SF3B1 cause additional epigenetic aberrations during carcinogenesis.

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IRF4 modulates the response to BCR activation in chronic lymphocytic leukemia regulating IKAROS and SYK

Cited by 16 publications

References 47 publications

Reduced IRF4 expression promotes lytic phenotype in Type 2 EBV-infected B cells

Reduced IRF4 expression promotes lytic phenotype in Type 2 EBV-infected B cells

Interferon Regulatory Factor 4 Correlated With Immune Cells Infiltration Could Predict Prognosis for Patients With Lung Adenocarcinoma

Altered DNA Methylation Profiles in SF3B1 Mutated CLL Patients

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