Impaired B Cell Development in the Absence of Krüppel-like Factor 3

Vũ, Thị Thanh Huyền; Gatto, Dominique; Turner, Vivian; Funnell, Alister P. W.; Mak, Ka Sin; Norton, Laura J.; Kaplan, Warren; Cowley, Mark J.; Agenès, Fabien; Kirberg, Jörg; Brink, Robert; Pearson, Richard; Crossley, Merlin

doi:10.4049/jimmunol.1101450

Cited by 39 publications

(50 citation statements)

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“…Further, Eμ-Bcl-3 mice exhibit a significant increase in GC B cells, while we detected a significant reduction of GC B cells, also upon immunization (data not shown). The phenotypically differences between mice that overexpress Bcl-3 in B and T cells and our mouse strain most probably depend on cooperative effects between Tg B and Tg T cells.Genetic mutations that cause changes in the composition of MZ B cells frequently lead also to changes in the composition of B-1 B cells as well [24]. Indeed, we show here a significant reduction of peritoneal B-1 B cells following overexpression of Bcl-3 in B cells.…”

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Overexpression of Bcl‐3 inhibits the development of marginal zone B cells

et al. 2013

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The transcription factor Bcl-3 functions as a proto-oncogene via regulation of cell proliferation and apoptosis. Bcl-3 is an atypical member of the IκB family and plays a central role in the immune response through interactions with the NF-κB subunits p50 and p52. To investigate the impact of Bcl-3 on B-cell maturation and regulation, we generated mice that overexpress Bcl-3 specifically in B cells. Interestingly, these mice lack marginal zone B cells and exhibit a significant reduction in the number of B-1 B cells. Further, B cells from these mice are impaired in their proliferative capacity. Our data demonstrate that the overexpression of the transcription factor Bcl-3 inhibits germinal center formation, marginal zone B-cell development, and affects the B-1 B-cell compartment.Keywords: B-1 B cells r Bcl-3 r Marginal zone B cell r NF-κB Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe Bcl-3 gene was first identified in a translocation into the Ig alpha locus in various cases of B-cell chronic lymphocytic leukemia [1,2]. The oncogene Bcl-3 encodes for an atypical member of the inhibitor of kappa B (IκB) family of proteins. Although Bcl-3 has high structural homology to the other IκB family members, Bcl-3 fails to inhibit NF-κB molecules in the cytoplasm but instead is a nuclear protein with both activating and repressing functions [3,4]. Specific domains within Bcl-3 can stimulate transcription through interaction with p50 and p52 homodimers [3,5]. So far Bcl-3 has also been implicated in various gene regulatory networks and biological processes [6,7] but its physiological mechanisms of action and in vivo targets remain largely unknown.Correspondence: Dr. Nadine Hövelmeyer e-mail: hoevelme@uni-mainz. de In order to study the role of Bcl-3 in lymphoid malignancies, Tg animals were generated overexpressing Bcl-3 in B and T cells. These mice exhibit splenomegaly and an accumulation of mature B cells in secondary lymphoid organs, but fail to develop lymphoid neoplasms. These mice show an increased response to crosslinking of surface IgM [8]. On the other hand, Bcl-3-deficient mice demonstrate the requirement for Bcl-3 in germinal center (GC) formation and in the production of Ag-specific antibodies [9,10]. Naïve B cells are generally divided into three subsets, B-1 B cells, follicular (FO), and marginal zone (MZ) B cells, whereas MZ B cells play a central role in eliciting Ab response against bloodborn pathogens. These B cells reside within the MZ located outside the marginal sinus and are the juncture of white and red pulp in the spleen. The factors that regulate the homeostasis of MZ B cells are not completely understood. Immature B cells that emigrate * These authors contributed equally to this work. from the bone marrow into the spleen develop through distinct transitional B-cell stages, termed as T1, T2, and T3 [11]. The T2 transitional B cell is thought to be the common precursor for both MZ and FO B cells [12]. FO B cells can b...

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Overexpression of Bcl‐3 inhibits the development of marginal zone B cells

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“…Comparing follicular and MZ B cells of normal and CD19:KLF3 transgenic mice by mRNA array analysis, b 7 integrin was strongly downregulated in KLF3 transgenic cells while being somewhat higher expressed in the absence of KLF3 (7,9). Thus, it was tested whether KLF3 represses b 7 as determined by cell surface staining.…”

Section: Klf3 Represses B 7 Integrin Expression In Vivomentioning

confidence: 99%

“…When constitutively expressed under the B cell-specific CD19 promoter, KLF3 increases maturation toward marginal zone (MZ) B cells, resulting in a 5-to 10-fold increase of this subset, whereas, accordingly, MZ B cells were reduced in KLF3-deficient mice (7,9). Interestingly, absence of KLF2 in B cells results in an increase of MZ B cells, mimicking the effect of constitutive KLF3 expression (15,16,19).…”

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“…However, more recent data in murine cells implicate KLF3 as a repressor of transcription (7)(8)(9). Indeed, KLF3 has been shown to interact with the common transcriptional corepressors C-terminal binding protein 2 (CtBP2) and four and a half LIM domain protein 3 (FHL3) (8,10,11).…”

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“…In lymphocytes, KLFs play important roles in their development and function (7,9,(13)(14)(15)(16)(17)(18)(19)(20). When constitutively expressed under the B cell-specific CD19 promoter, KLF3 increases maturation toward marginal zone (MZ) B cells, resulting in a 5-to 10-fold increase of this subset, whereas, accordingly, MZ B cells were reduced in KLF3-deficient mice (7,9).…”

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Leukocyte β7 Integrin Targeted by Krüppel-like Factors

Alles

Turchinovich

Zhang

et al. 2014

The Journal of Immunology

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Constitutive expression of Krüppel-like factor 3 (KLF3, BKLF) increases marginal zone (MZ) B cell numbers, a phenotype shared with mice lacking KLF2. Ablation of KLF3, known to interact with serum response factor (SRF), or SRF itself, results in fewer MZ B cells. It is unknown how these functional equivalences result. In this study, it is shown that KLF3 acts as transcriptional repressor for the leukocyte-specific integrin β7 (Itgb7, Ly69) by binding to the β7 promoter, as revealed by chromatin immunoprecipitation. KLF2 overexpression antagonizes this repression and also binds the β7 promoter, indicating that these factors may compete for target sequence(s). Whereas β7 is identified as direct KLF target, its repression by KLF3 is not connected to the MZ B cell increase because β7-deficient mice have a normal complement of these and the KLF3-driven increase still occurs when β7 is deleted. Despite this, KLF3 overexpression abolishes lymphocyte homing to Peyer’s patches, much like β7 deficiency does. Furthermore, KLF3 expression alone overcomes the MZ B cell deficiency when SRF is absent. SRF is also dispensable for the KLF3-mediated repression of β7. Thus, despite the shared phenotype of KLF3 and SRF-deficient mice, cooperation of these factors appears neither relevant for the formation of MZ B cells nor for the regulation of β7. Finally, a potent negative regulatory feedback loop limiting KLF3 expression is shown in this study, mediated by KLF3 directly repressing its own gene promoter. In summary, KLFs use regulatory circuits to steer lymphocyte maturation and homing and directly control leukocyte integrin expression.

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Expression of human Krüppel‐like factor 3 in peripheral blood as a promising biomarker for acute leukemia

Yan

Liu

et al. 2020

Cancer Medicine

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Background: Universal gene targets are in persistent demand by real-time quantitative polymerase chain reaction (RT-qPCR)-based methods in acute leukemia (AL) diagnosis and monitoring. Human Krüppel-like factor 3 (hKLF3), a newly cloned human transcription factor, has proved to be a regulator of hematopoiesis. Methods: Sanger sequencing was performed in bone marrow (BM) samples from 17 AL patients for mutations in hKLF3 coding exons. hKLF3 expression in peripheral blood (PB) and BM samples from 45 AL patients was dynamically detected by RT-qPCR. PB samples from 31 healthy donors were tested as normal controls. Results: No mutation was sequenced in hKLF3 coding exons. hKLF3 expression in PB of AL was significantly lower than that in healthy donors [0.30 (0.02-1.07) vs 1.18 (0.62-3.37), P < .0001]. Primary acute myeloid leukemia (AML) exhibited the least expression values compared with secondary AML and acute lymphoblastic leukemia. Receiver operating characteristic (ROC) analyses suggested that hKLF3expression in PB was a good marker for AML diagnosis with an AUC of 0.99 (95% CI 0.98-1.00) and an optimum cutoff value of 0.67 (sensitivity 93.94% and specificity 93.55%). hKLF3 expression was upregulated significantly when AML patients acquired morphological complete remission (CR), and the level of hKLF3 seemed to be higher in patients with deeper CR than in patients with minimal residual disease (MRD). Paired PB and BM samples showed highly consistent alteration in hKLF3 expression (r = .6533, P = .001). Besides, a significantly converse correlation between decreased hKLF3 expression in PB and markers for leukemic load was observed. Conclusions: hKLF3 expression in PB may act as a potential marker for AL diagnosis and monitoring. K E Y W O R D Sacute leukemia, biomarker, diagnosis, human krüppel-like factor 3, minimal residual disease 2804 | YAN et Al.

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Impaired B Cell Development in the Absence of Krüppel-like Factor 3

Cited by 39 publications

References 58 publications

Overexpression of Bcl‐3 inhibits the development of marginal zone B cells

Overexpression of Bcl‐3 inhibits the development of marginal zone B cells

Leukocyte β7 Integrin Targeted by Krüppel-like Factors

Expression of human Krüppel‐like factor 3 in peripheral blood as a promising biomarker for acute leukemia

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