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: 19.75). 04/2007; 26(3):335-44. DOI: 10.1016/j.immuni.2007.02.010
Source: PubMed

ABSTRACT 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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    • "This suggests that not only does Ikaros regulate signaling through lymphocyte receptors, but lymphocyte receptor signaling can also control the expression of Ikaros family members. The pre-BCR-to-Aiolos feedback loop depends on a specific branch of pre-BCR signaling mediated by the adapter adaptor protein SH2-domain-containing leukocyte protein of 65 kDa, SLP65 [20]. The interferon regulatory factors 4 and 8 may mediate between SLP65 and Aiolos [47]. "
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    ABSTRACT: Ikaros is the founding member of a family of transcription factors. Ikaros proteins are required for the normal development of lymphocytes and other blood cell lineages, and have an important role in haematopoietic malignancies. Accumulating data link Ikaros to immune receptor rearrangement and signaling, and the balance between proliferation and differentiation of immune cells. The emerging picture is that Ikaros family members are critical for a functional immune system that confers protection against invading pathogens, while minimising the risk of leukaemic transformation, immune pathology, and autoimmunity.
    FEBS letters 09/2010; 584(24):4910-4. DOI:10.1016/j.febslet.2010.09.042 · 3.34 Impact Factor
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    • "Ikaros family transcription factors – especially Ikaros and Aiolos are required for B cell development to progress ( Thompson et . al , 2007 ) . B and T cell development is arrested in Ikaros - deficient mice with abnormal myelopoeisis ( Wang et . al . , 1996 ) ."
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    • "As mentioned above, noticeably, the Aiolos gene is widely expressing through the normal developmental stage from pro-B cells to mature B cells [7] [8]. Recently, Thompson et al. showed that pre-BCR signaling regulates Aiolos expression via the adaptor protein SLP-65 [17]. In addition, it has been reported that Aiolos is up-regulated in chronic lymphocytic leukemia [18]. "
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