Essential role of EBF1 in the generation and function of distinct mature B cell types

Vilagos, Bojan; Hoffmann, Marc P.; Souabni, Abdallah; Sun, Qiong; Werner, Barbara; Medvedovic, Jasna; Bilić, Ivan; Minnich, Martina; Axelsson, Elin; Jaritz, Markus; Busslinger, Meinrad

doi:10.1084/jem.20112422

Cited by 118 publications

(129 citation statements)

References 82 publications

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“…EBF1 has been shown to be crucial for B cell development (54). Furthermore, it was demonstrated to be required for B cell commitment, pro-B cell development, and subsequent transition to the pre-B cell stage (55). Lack of this molecule leads to loss of B cells at the pre-B cell step, which reflects our observations in Dkk3 2/2 mice (54).…”

Section: Discussionsupporting

confidence: 79%

Dickkopf-3 Acts as a Modulator of B Cell Fate and Function

Ludwig

Federico

Prokosch

et al. 2015

The Journal of Immunology

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The mechanisms responsible for the generation of a mature B1 and B2 cell compartment are still poorly understood. In this study, we demonstrated that absence of Dickkopf-3 (DKK3) led to changes in the composition of the B cell compartment, which were due to an altered development and maintenance program of B cells. Development of B2 cells was impaired at the pre- and immature B cell stage, resulting in decreased numbers of follicular B cells in adult DKK3-deficient mice. Furthermore, DKK3 limited B1 cell self-maintenance in the periphery, by decreasing the survival and proliferation behavior of B1 cells. DKK3 may act via the BCR signaling pathway, as Ca2+ influx upon BCR stimulation was increased and SiglecG, a molecule shown to inhibit Calcium signaling, was downregulated in the absence of DKK3. DKK3-deficient mice exhibited altered Ab responses and an increased secretion of the cytokine IL-10. Additionally, DKK3 limited autoimmunity in a model of systemic lupus erythematosus. In summary, we identified DKK3 as a novel modulator interfering with B cell fate as well as the maintenance program of B cells, leading to changes in B cell immune responses.

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Section: Discussionsupporting

confidence: 79%

Dickkopf-3 Acts as a Modulator of B Cell Fate and Function

Ludwig

Federico

Prokosch

et al. 2015

The Journal of Immunology

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“…16 The finding that the developmental block observed in Pax5-deficient leukemia cells can be reversed on restoration of Pax5 expression suggests that the reduction in Pax5 function results in a reversible disruption of differentiation. 17 A similar mechanism of action has been proposed for Ebf1; however, reduced amounts of Ebf1 in normal cells appear to result in reduced proliferation and expansion of B-cell progenitors, 4,6,18,19 indicating that the involvement of EBF1 in malignant transformation is more complex.…”

Section: Cd43mentioning

confidence: 74%

“…4,18,19 To understand more about how Ebf1 dose impacts cellular functions in B-cell development, we analyzed gene expression data from primary sorted CD19 1 immunoglobulin (Ig)M -B-cell progenitors from Wt and Ebf1 1/2 mice. 6 Gene expression data from CD43 low/neg progenitors revealed reduced expression of Rad51, Rad51ap1, and Smc2, all coding for proteins with functions in DNA repair, whereas the mRNA levels for the antiapoptotic Bcl2 protein were increased.…”

Section: Resultsmentioning

confidence: 99%

Ebf1 heterozygosity results in increased DNA damage in pro-B cells and their synergistic transformation by Pax5 haploinsufficiency

Prasad¹,

Ungerbäck²,

Åhsberg³

et al. 2015

Blood

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“…Twelve were known oncogenes (including BCL2, 4 RUNX1, 21 and KDSR, 22 and were also found translocated and/or amplified in 100%, 70% and 30% of our series of FL samples, respectively (Online Supplementary Table S3). Four amplified genes (TOX, BACH2, 23 AFF3, 24 and EBF1, 25 Online Supplementary Figure S4) were functionally related to the GC reaction, and were also found amplified in 100%, 90%, 80%, and 70% of FL, respectively. Notably, gain of AFF3 was recurrently found in two distinct FLIS samples.…”

Section: Follicular Lymphoma In Situmentioning

confidence: 99%

Early lesions of follicular lymphoma: a genetic perspective

Mamessier¹,

Song

Éberlé

et al. 2013

Haematologica

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© F e r r a t a S t o r t i F o u n d a t i o nposed to distinguish FLIS from partial involvement by FL (PFL). In PFL there is greater architectural distortion, and the diagnosis of lymphoma is more evident histologically. However, interestingly, patients with PFL appear to present with low-stage disease, with a relatively low risk of progression and often a very prolonged disease-free interval with limited therapy. 12 Thus, PFL may represent a bona fide early stage in the biological evolution of FL, and not just a limited state of lymph node replacement by a fully developed neoplasm.14 Advances in laser capture microdissection now enable the isolation of even small numbers of cells representative of the clonotypic population, 15 and improvements in genomic methods allow the analysis of genetic aberrations in DNA derived from formalin-fixed, paraffin-embedded tissues. These new technologies now provide the unique opportunity to explore the genetic landscape of these early lesions, and to understand their relationship to overt FL better. Methods SamplesMost cases were selected from formalin-fixed, paraffin-embedded archive specimens submitted to the Hematopathology Section at the National Cancer Institute (NCI) or the Institute of Pathology, at the Medical University of Vienna. Seven cases of FLIS, five cases of PFL and five cases of DFL were identified based on previously published criteria. 11,12 Patients with FLIS and PFL had no other evidence of disease during the period of follow-up. 12 These samples were compared to five cases of FL grade 1-2 and five of FL grade 3A, included as controls of the most frequent alterations occurring in FL. Finally, sections of reactive follicular hyperplasia (RFH, n=2) and laser micro-dissected lymphoid cells from uninvolved areas of FLIS#3 (FLIS background) were also hybridized and used as references for normal cells (Online Supplementary Table S1). Only cases with confirmed t(14;18) were included in the study. The Institutional Review Boards of the NCI and the Medical University of Vienna approved the study. Laser capture microdissection, DNA extraction and quality controlTo obtain sufficient enrichment of lesional cells positive for t(14;18), which was necessary for the genome-wide array analysis, BCL2 + GC were microdissected from the selected FLIS/PFL/DFL/FL grade 1-2 cases. Laser capture microdissection was performed using a Leica LMD6000 (Leica Microsystems, Germany) on hematoxylin-stained slides with BCL2 + immunostained slides as a guide for involved follicles.15 BCL2-negative GC were microdissected from RFH, without evidence of FLIS. Tumor cell DNA was isolated from FL grade 3A without microdissection, given the high tumor cell content (>75%). DNA was extracted using a QIAamp ® DNA FFPE Kit. The amount of DNA collected from the different cases ranged from 506 to 2820 ng. With a calculation of 6.6 pg of DNA/cell this amounts to a minimum of 77,000 cells per case needed for appropriate hybridization. The integrity of the DNA was controlled with an Agilent DNA1...

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Essential role of EBF1 in the generation and function of distinct mature B cell types

Abstract: Gain- and loss-of-function analyses reveal that the transcription factor EBF1 is required for normal differentiation and function of marginal zone, B-1, follicular, and germinal center B cells in mice.

Cited by 118 publications

References 82 publications

Dickkopf-3 Acts as a Modulator of B Cell Fate and Function

Dickkopf-3 Acts as a Modulator of B Cell Fate and Function

Ebf1 heterozygosity results in increased DNA damage in pro-B cells and their synergistic transformation by Pax5 haploinsufficiency

Early lesions of follicular lymphoma: a genetic perspective

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