Ikaros is critical for B cell differentiation and function

Kirstetter, Peggy; Thomas, Mireille; Dierich, Andrée; Kastner, Philippe; Chan, Susan

doi:10.1002/1521-4141(200203)32:3<720::aid-immu720>3.0.co;2-p

Cited by 137 publications

(117 citation statements)

References 29 publications

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“…Whereas peripheral B cell populations are largely phenotypically normal in young Vk2-Ik7tg mice, abnormal populations (B220 lo IgM -and B220 lo IgM + ) appear in older mice, leading to a corresponding decrease in the percentage of phenotypically normal B220 + IgM + mature B cells. In Ik L/L mice, B220 levels are decreased on the surface of bone marrow B cells, although this is not observed in the periphery as is observed in the aging Vk2-Ik7tg mice [2]. Nevertheless, this similarity in phenotype may suggest a direct or indirect role for Ikaros in regulation of the CD45 gene, which encodes B220.…”

Section: Altered Lymphocyte Populations But No Leukemogenesis In Old mentioning

confidence: 84%

“…Much evidence exists that Ikaros can function as a tumor suppressor in the T cell lineage. Ikaros DN +/-and Ik L/L mice, models in which Ikaros activity has been diminished through homologous recombination to create mutant alleles, share a common phenotype of 100% incidence of T cell leukemogenesis [2,4]. Since these are germ-line mutations, diminution of Ikaros activity occurs in all cells in which Ikaros is expressed.…”

Section: Altered Lymphocyte Populations But No Leukemogenesis In Old mentioning

confidence: 99%

“…In addition to defects in B cell development, Ik-null and Ik L/L mice develop T cell leukemia with 100% penetrance [1,2]. This phenotype is also observed in a third genetically engineered Ikaros mutant mouse line in which targeted deletion of exons 3 and 4 of the Ikaros gene results in high-level expression of non-DNAbinding Ikaros proteins from the targeted allele [3,4].…”

Section: Introductionmentioning

confidence: 97%

“…Mice engineered to lack Ikaros (Ik-null mice) display a complete block in B cell development, making study of the role of Ikaros in B cell development and function difficult to impossible in this system [1]. In a second genetically engineered line of mice, Ik L/L mice, a b-galactosidase reporter gene was inserted into exon 2 of the Ikaros locus [2]. These mice express very low levels of a mutant Ikaros protein that lacks exon 2.…”

Section: Introductionmentioning

confidence: 99%

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Expression of a non‐DNA‐binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis

et al. 2007

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Ikaros is a transcriptional regulator whose function is essential for B cell development. It is expressed in the hematopoietic stem cell (HSC) through the mature B cell stage. Using genetically engineered mice in which the endogenous Ikaros gene is disrupted, it has been shown that a lack of Ikaros leads to a block in B cell development and that its severe diminution results in a hyperresponsive B cell compartment. Ikaros expression within the HSC has led to speculation as to whether the role of Ikaros in B cell biology is largely accomplished prior to B cell specification. In addition, widespread expression of Ikaros in hematopoietic cells leads to the possibility that some or all of the observed defects are not B cell autonomous. In this report, we demonstrate that over-expression of a dominant interfering Ikaros isoform exclusively in B cells has profound effects on mature B cell function. We provide evidence that continued high-level expression of Ikaros is essential for homeostasis of peripheral lymphocytes and maintenance of B cell tolerance. We also show that deregulation of Ikaros activity does not rapidly result in B cell leukemogenesis as it does with 100% penetrance within the T cell lineage.

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Section: Altered Lymphocyte Populations But No Leukemogenesis In Old mentioning

confidence: 84%

Section: Altered Lymphocyte Populations But No Leukemogenesis In Old mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Expression of a non‐DNA‐binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis

et al. 2007

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“…Ikaros had been previously targeted and analysis of a null allele, a hypomorphic allele, and a dominant negative allele had shown that Ikaros was involved in lymphocyte, B cell, and natural killer cell development (Georgopoulos et al, 1994;Wang et al, 1996;Kirstetter et al, 2002). The ENU-induced allele, Ikaros plastic , showed defects in the formation of additional blood cell types including erythrocytes, granulocytes, and macrophages.…”

Section: Types Of Mutations and Allelic Seriesmentioning

confidence: 99%

Uncovering the uncharacterized and unexpected: Unbiased phenotype‐driven screens in the mouse

Caspary

Anderson

2006

Developmental Dynamics

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Phenotype-based chemical mutagenesis screens for mouse mutations have undergone a transformation in the past five years from a potential approach to a practical tool. This change has been driven by the relative ease of identifying causative mutations now that the complete genome sequence is available. These unbiased screens make it possible to identify genes, gene functions and processes that are uniquely important to mammals. In addition, because chemical mutagenesis generally induces point mutations, these alleles often uncover previously unappreciated functions of known proteins. Here we provide examples of the success stories from forward genetic screens, emphasizing the examples that illustrate the discovery of mammalian-specific processes that could not be discovered in other model organisms. As the efficiency of sequencing and mutation detection continues to improve, it is likely that forward genetic screens will provide an even more important part of the repertoire of mouse genetics in the future. Developmental Dynamics 235:2412-2423, 2006.

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Ikaros has a crucial role in regulation of B cell receptor signaling

et al. 2006

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The transcription factor Ikaros, a key regulator of hematopoiesis, has an essential role in lymphocyte development. In mice, fetal lymphoid differentiation is blocked in the absence of Ikaros, and whereas T cells develop postnatally, B cells are totally absent. The significance of Ikaros in the B cell development is evident, but how Ikaros regulates B cell function has neither been established nor previously been studied with B cells that lack Ikaros expression. Here we show that disruption of Ikaros in the chicken B cell line DT40 induces a B cell receptor (BCR) signaling defect with reduced phospholipase Cc2 phosphorylation and impaired intracellular calcium mobilization, which is restored by Ikaros reintroduction. Furthermore, we show that lack of Ikaros induces hyperphosphorylation of Casitas B lymphoma protein subsequent to BCR activation. These results indicate that the absolute need of Ikaros for development, cell fate decisions and maintenance of B cells is due to the enhancement of BCR signaling.

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Ikaros is critical for B cell differentiation and function

Cited by 137 publications

References 29 publications

Expression of a non‐DNA‐binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis

Expression of a non‐DNA‐binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis

Uncovering the uncharacterized and unexpected: Unbiased phenotype‐driven screens in the mouse

Ikaros has a crucial role in regulation of B cell receptor signaling

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