Ikaros DNA-Binding Proteins as Integral Components of B Cell Developmental-Stage-Specific Regulatory Circuits

Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College London, Du Cane Road, London W12 0NN, UK.
Immunity (Impact Factor: 21.56). 04/2007; 26(3):335-44. DOI: 10.1016/j.immuni.2007.02.010
Source: PubMed


Ikaros DNA-binding proteins are critical for the development of lymphocytes and other hematopoietic lineages, but it remains unclear how they cooperate with other regulators of signaling and transcription to achieve ordered gene expression during development. Here, we show that Ikaros proteins regulate the pre-BCR component lambda5 in a stage-specific manner. In pre-BI cells, Ikaros modulated lambda5 expression in competition with the transcriptional activator EBF. This required Ikaros binding to the Igll1 (lambda5) promoter and was abolished either by mutation of the Ikaros DNA-binding domain or by deletion of a single Ikaros site from the Igll1 promoter. At the transition from the pre-BI to pre-BII stage, the expression of the Ikaros family member Aiolos was upregulated and required for the efficient silencing of Igll1. Aiolos expression was controlled by pre-BCR signals via the adaptor protein SLP-65. Thus, pre-BCR signaling regulates Aiolos and the silencing of Igll1 via a developmental-stage-specific feedback loop.

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Available from: Pierangela Sabbattini, Feb 19, 2014
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    • "KLF4, a closely related transcription factor, is still present in KLF2-deficient pre-B cells. Therefore, we propose that KLF4, due to its overlapping set of target genes, compensates for the loss of KLF2 and terminates pre-B cell proliferation together with Ikaros/Aiolos [28]. To address this issue in vivo, analysis of KLF2/KLF4 double knockout mice will provide a deeper insight into the mechanisms by which KLF2 and KLF4 regulate B cell proliferation, migration and quiescence. "
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    ABSTRACT: Maturation as well as antigen-dependent activation of B cells is accompanied by alternating phases of proliferation and quiescence. We and others have previously shown that Krüppel-like factor 2 (KLF2), a regulator of T cell quiescence and migration, is upregulated in small resting precursor (pre)-B cells after assembly of the immature pre-B cell receptor (pre-BCR) and is downregulated upon antigen-induced proliferation of mature B cells. These findings suggest that KLF2, besides its function in maintaining follicular B cell identity, peripheral B cell homeostasis and homing of antigen-specific plasma cells to the bone marrow, also controls clonal expansion phases in the B cell lineage. Here, we demonstrate that enforced expression of KLF2 in primary pre-B cells results in a severe block of pre-BCR-induced proliferation, upregulation of the cell cycle inhibitors p21 and p27 and downregulation of c-myc. Furthermore, retroviral KLF2 transduction of primary B cells impairs LPS-induced activation, favors apoptosis and results in reduced abundance of factors, such as AID, IRF4 and BLIMP1, that control the antigen-dependent phase of B cell activation and plasma cell differentiation. Hence, we conclude that KLF2 is not only a key player in terminating pre-B cell clonal expansion but also a potent suppressor of B cell activation.
    PLoS ONE 05/2014; 9(5):e97953. DOI:10.1371/journal.pone.0097953 · 3.23 Impact Factor
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    • "FoxO1 represses surface expression of IL-7R in pre-B cells, while BLNK inhibits PI3K/Akt activation (52, 71). Pre-BCR signals also induce the expression of the transcription factors Aiolos and Ikaros (77, 78). These factors impede cell cycle by repression of Myc and cyclin D3 gene expression (23, 78). "
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    ABSTRACT: The essential events of B-cell development are the stochastic and sequential rearrangement of immunoglobulin heavy (Igμ) and then light chain (Igκ followed by Igλ) loci. The counterpoint to recombination is proliferation, which both maintains populations of pro-B cells undergoing Igμ recombination and expands the pool of pre-B cells expressing the Igμ protein available for subsequent Igκ recombination. Proliferation and recombination must be segregated into distinct and mutually exclusive developmental stages. Failure to do so risks aberrant gene translocation and leukemic transformation. Recent studies have demonstrated that proliferation and recombination are each affected by different and antagonistic receptors. The IL-7 receptor drives proliferation while the pre-B-cell antigen receptor, which contains Igμ and surrogate light chain, enhances Igκ accessibility and recombination. Remarkably, the principal downstream proliferative effectors of the IL-7R, STAT5 and cyclin D3, directly repress Igκ accessibility through very divergent yet complementary mechanisms. Conversely, the pre-B-cell receptor represses cyclin D3 leading to cell cycle exit and enhanced Igκ accessibility. These studies reveal how cell fate decisions can be directed and reinforced at each developmental transition by single receptors. Furthermore, they identify novel mechanisms of Igκ repression that have implications for gene regulation in general.
    Frontiers in Immunology 04/2014; 5:139. DOI:10.3389/fimmu.2014.00139
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    • "IK is a zinc finger-containing DNA-binding protein that plays a pivotal role in immune homeostasis through transcriptional regulation of the earliest stages of lymphocyte ontogeny by both (a) gene transcriptional activation via efficient transcription initiation and elongation as well as (b) gene repression [10]–[12], [26]. IK also exhibits a tumor suppressor function in lymphocyte precursors, which has been attributed in part to its ability to repress expression of oncogenic genes via chromatin remodeling in association with the SWI/SNF remodeling complex and recruitment of potentially oncogenic proliferation-promoting genes to pericentromeric heterochromatin (PC-HC) [10]–[12], [26], [30]. Impaired DNA binding activity of IK has been associated with a release of NuRD from IK target genes to cause both a maturational arrest in lymphocyte ontogeny and an “illegitimate” activation of a network of genes that promote leukemogenesis [30]. "
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    ABSTRACT: Diminished Ikaros function has been implicated in the pathogenesis of acute lymphoblastic leukemia (ALL), the most common form of childhood cancer. Therefore, a stringent regulation of Ikaros is of paramount importance for normal lymphocyte ontogeny. Here we provide genetic and biochemical evidence for a previously unknown function of Bruton's tyrosine kinase (BTK) as a partner and posttranslational regulator of Ikaros, a zinc finger-containing DNA-binding protein that plays a pivotal role in immune homeostasis. We demonstrate that BTK phosphorylates Ikaros at unique phosphorylation sites S214 and S215 in the close vicinity of its zinc finger 4 (ZF4) within the DNA binding domain, thereby augmenting its nuclear localization and sequence-specific DNA binding activity. Our results further demonstrate that BTK-induced activating phosphorylation is critical for the optimal transcription factor function of Ikaros.
    PLoS ONE 08/2013; 8(8):e71302. DOI:10.1371/journal.pone.0071302 · 3.23 Impact Factor
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