Initiation of Antigen Receptor-Dependent Differentiation into Plasma Cells by Calmodulin Inhibition of E2A

Hauser, Jannek; Verma-Gaur, Jiyoti; Wallenius, Anders; Grundström, Thomas

doi:10.4049/jimmunol.0900455

Cited by 22 publications

(24 citation statements)

References 34 publications

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“…Known to be involved in the pathogenesis of multiple human cancers, 12,13 both ETS1 and FLI1 have an important role in the development of lymphoid tissues and immune system control, [14][15][16] regulating the activity of important players in B-cell growth and maturation such as the B-cell-specific activator protein PAX5 19 Notably, Ets1 and Fli1 are repressed during the late phases of B-cell differentiation in an in vitro murine system. 20 Here, we show that the 11q24.3 genomic lesion correlates with high levels of ETS1 and FLI1 expression in human DLBCL primary samples. Moreover, we demonstrated, in an in vitro model, that both ETS1 and FLI1 are critical for cell viability and that they regulate genes that are controlling the normal GC B-cell differentiation.…”

Section: Introductionmentioning

confidence: 93%

“…19 Notably, Ets1 and Fli1 are repressed during the late phases of B-cell differentiation in an in vitro murine system. 20 Here, we show that the 11q24.3 genomic lesion correlates with high levels of ETS1 and FLI1 expression in human DLBCL primary samples. Moreover, we demonstrated, in an in vitro model, that both ETS1 and FLI1 are critical for cell viability and that they regulate genes that are controlling the normal GC B-cell differentiation.…”

Section: Introductionmentioning

confidence: 93%

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Deregulation of ETS1 and FLI1 contributes to the pathogenesis of diffuse large B-cell lymphoma

Bonetti

Testoni

Scandurra

et al. 2013

Blood

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Key Points• A recurrent gain of a region of chromosome 11 (11q24.3) occurs in up to one-quarter of cases of diffuse large B-cell lymphoma.• ETS1 and FLI1 genes are overexpressed and determine proliferation, survival, and differentiation arrest of the lymphoma cells.Diffuse large B-cell lymphoma (DLBCL) is the most common form of human lymphoma. DLBCL is a heterogeneous disease characterized by different genetic lesions. We herein report the functional characterization of a recurrent gain mapping on chromosome 11q24.3, found in 23% of 166 DLBCL cases analyzed. The transcription factors ETS1 and FLI1, located within the 11q24.3 region, had significantly higher expression in clinical samples carrying the gain. Functional studies on cell lines showed that ETS1 and FLI1 cooperate in sustaining DLBCL proliferation and viability and regulate genes involved in germinal center differentiation. Taken together, these data identify the 11q24.3 gain as a recurrent lesion in DLBCL leading to ETS1 and FLI1 deregulated expression, which can contribute to the pathogenesis of this disease. (Blood. 2013;122(13):2233-2241) IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, accounting for 25% to 30% of adult cases in western countries, and it is characterized by heterogeneous histopathological, biological, and clinical features.1 DLBCL has been molecularly classified in at least 3 subtypes, reflecting different stages of B-cell differentiation: germinal center B-cell-like DLBCL (GCB) from germinal center (GC) centroblasts, activated B-cell-like DLBCL (ABC) from GC cells undergoing plasmacytic differentiation, and an intermediate type 3 DLBCL. 2 Physiological GC B-cell differentiation requires a complex transcriptional program and DLBCL displays recurrent genetic abnormalities that typically circumvent this normal genetic program, allowing the neoplastic B cells to avoid plasmacytic differentiation and evade apoptosis.2 Briefly, chromosomal translocations involving the BCL2 oncogene and mutations of the EZH2 methyltransferase are almost exclusively observed in GCB DLBCL, 3 whereas ABC DLBCL are preferentially associated with a disruption of terminal B-cell differentiation program (ie, PRDM1 inactivation and BCL6 deregulation) 4,5 and constitutive activation of the nuclear factor kB (NF-kB) transcription pathway (most commonly via somatic mutations of TNFAIP3, CARD11, CD79B, and MYD88). [6][7][8] Other recurrent lesions can be found in all the DLBCL subtypes, including inactivation of histone and/or chromatin modifying genes CREBBP, EP300, and MLL2 9,10 and of genes involved in immune recognition, such as b2-microglobulin and CD58. 11 It is likely that additional, undescribed genetic defects may also contribute to the pathogenesis of DLBCL.In the present study, aimed to identify new recurrent genetic defects in DLBCL, we performed genomic profiling analysis on 166 DLBCL samples, which enabled us to characterize a new recurrent lesion on chromosome 11q24.3 occurring in up to onequarter of...

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Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 93%

Deregulation of ETS1 and FLI1 contributes to the pathogenesis of diffuse large B-cell lymphoma

Bonetti

Testoni

Scandurra

et al. 2013

Blood

View full text Add to dashboard Cite

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“…These results were consistent with reports on lymph nodes. [10][11][12][13][14][15][16][17] The restricted expression of E2A in the follicles was also consistent with its function in inducing somatic hypermutations.…”

Section: E2a Was Expressed On the Follicular But Not The Marginal-zonmentioning

confidence: 59%

“…12 Aberrant E2A Expression Was Associated with Less Plasmacytoid Infiltrates Gastric MALT lymphomas, which are mainly composed of centrocyte-like lymphoma cells, frequently have plasma cell differentiation. As one of the biological effects of E2A is to block plasma cell differentiation, aberrant E2A expression in gastric MALT lymphomas might be associated with decreased numbers of plasma cells.…”

Section: E2a Was Expressed On the Follicular But Not The Marginal-zonmentioning

confidence: 99%

“…10,11 Furthermore, down-regulation of E2A is required for differentiation of germinalcenter B cells into plasma cells. 12 Therefore, expression of E2A on gastric MALT lymphoma might be a potential marker of aberrant follicular differentiation, and might be associated with either an increase in somatic hypermutations or a block in terminal plasma cell differentiation.…”

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confidence: 99%

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E2A-positive gastric MALT lymphoma has weaker plasmacytoid infiltrates and stronger expression of the memory B-cell-associated miR-223: possible correlation with stage and treatment response

et al. 2010

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Extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue of the stomach (gastric MALT lymphoma) is derived from memory B cells of the marginal zone. Normal memory B cells do not express markers of germinal-center B cells, such as E2A (immunoglobulin enhancer-binding factor E12/E47), B-cell chronic lymphocytic leukemia/lymphoma 6 (BCL6), or activation-induced cytidine deaminase (AID). E2A is a transcription factor that induces somatic hypermutations and blocks plasma cell differentiation. In 50 stage-I E /II E1 gastric MALT lymphomas, we confirmed that all cases were BCL6 À /AID À , but a subset (50%, 25/50) was E2A þ . As E2A À and E2A þ gastric MALT lymphomas had similar numbers of somatic hypermutations without intraclonal variations, which implied an origin from memory B cells, the expression of E2A was best regarded as a marker of aberrant follicular differentiation. Although the status of somatic hypermutation was not affected by E2A, E2A þ gastric MALT lymphoma showed less plasmacytoid infiltrates and higher expressions of miRNA-223, a microRNA associated with memory B cells. Clinically, E2A þ gastric MALT lymphomas were more likely to spread to perigastric lymph nodes and were less responsive to Helicobacter eradication therapy than were E2A À gastric MALT lymphomas. Taken together, aberrant E2A expression is a diagnostic feature of a subtype of gastric MALT lymphoma with weaker plasmacytoid infiltrates and stronger miR-223 expression. A prospective study would be necessary to verify the association between E2A expression and a poor response to Helicobacter eradication therapy. Keywords: E2A; gastric MALT lymphoma; Helicobacter pylori eradication therapy; memory B cell; miR-223; plasma cell Extranodal marginal-zone lymphoma of mucosaassociated lymphoid tissue of the stomach (gastric MALT lymphoma) is a Helicobacter pylori infection-associated lymphoma that depends on the stimulus of Helicobacter for growth.1 About 70% of gastric MALT lymphomas can be cured by H. pylori eradication therapy with antibiotics, 2 but cases with API2-MALT1 fusion because of t(11;18)(q21; q21) or with nuclear expression of NFkB or B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL10) are unresponsive. 3,4 From the pathologists' perspective, gastric MALT lymphoma is an extranodal marginal-zone lymphoma.

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Epigenetic programming underpins B‐cell dysfunction in peanut and multi‐food allergy

et al. 2021

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Objective Rates of IgE‐mediated food allergy (FA) have increased over the last few decades, and mounting evidence implicates disruption of epigenetic profiles in various immune cell types in FA development. Recent data implicate B‐cell dysfunction in FA; however, few studies have examined epigenetic changes within these cells. Methods We assessed epigenetic and transcriptomic profiles in purified B cells from adolescents with FA, comparing single‐food‐allergic (peanut only), multi‐food‐allergic (peanut and ≥1 other food) and non‐allergic (control) individuals. Adolescents represent a phenotype of persistent and severe FA indicative of a common immune deviation. Results We identified 144 differentially methylated probes (DMPs) and 116 differentially expressed genes (DEGs) that distinguish B cells of individuals with FA from controls, including differential methylation of the PM20D1 promoter previously associated with allergic disorders. Subgroup comparisons found 729 DMPs specific to either single‐food‐ or multi‐food‐allergic individuals, suggesting epigenetic distinctions between allergy groups. This included two regions with increased methylation near three S100 genes in multi‐food‐allergic individuals. Ontology results of DEGs specific to multi‐food‐allergic individuals revealed enrichment of terms associated with myeloid cell activation. Motif enrichment analysis of promoters associated with DMPs and DEGs showed differential enrichment for motifs recognised by transcription factors regulating B‐ and T‐cell development, B‐cell lineage determination and TGF‐β signalling pathway between the multi‐food‐allergic and single‐food‐allergic groups. Conclusion Our data highlight epigenetic changes in B cells associated with peanut allergy, distinguishing features of the epigenome between single‐food‐ and multi‐food‐allergic individuals and revealing differential developmental pathways potentially underpinning these distinct phenotypes.

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Initiation of Antigen Receptor-Dependent Differentiation into Plasma Cells by Calmodulin Inhibition of E2A

Cited by 22 publications

References 34 publications

Deregulation of ETS1 and FLI1 contributes to the pathogenesis of diffuse large B-cell lymphoma

Deregulation of ETS1 and FLI1 contributes to the pathogenesis of diffuse large B-cell lymphoma

E2A-positive gastric MALT lymphoma has weaker plasmacytoid infiltrates and stronger expression of the memory B-cell-associated miR-223: possible correlation with stage and treatment response

Epigenetic programming underpins B‐cell dysfunction in peanut and multi‐food allergy

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