Disease relevance of Ikzf3

• These results do not suggest any obvious contribution of Helios or Aiolos to oncogenesis of the mouse thymic lymphomas [1].

High impact information on Ikzf3

• The follicular versus marginal zone B lymphocyte cell fate decision is regulated by Aiolos, Btk, and CD21 [2].
• Most splenic B cells in mice that lack Aiolos are mature IgD(hi)IgM(lo) follicular lymphocytes, suggesting that maturation signals delivered via the BCR are enhanced in the absence of Aiolos [2].
• Aiolos regulates B cell activation and maturation to effector state [3].
• Auto-antibodies and development of B cell lymphomas are frequently seen among aging Aiolos mutants [3].
• Aiolos encodes a zinc finger DNA-binding protein that is highly expressed in mature B cells and is homologous to Ikaros [3].

Biological context of Ikzf3

• However, 33 of the 34 lymphomas showing allelic loss at Aiolos were p53(KO / - ) and were accompanied by loss of the p53 wild-type allele on the same chromosome [1].
• The enhanced maturation of follicular B cells is accompanied by the absence of MZ B lymphocytes and the downregulation of CD21 expression in follicular B cells, all of which depend on the generation of signals via Btk, which is in epistasis to Aiolos [2].
• In the periphery of mice homozygous for an Aiolos-null mutation, B cells exhibit an activated cell surface phenotype and undergo augmented antigen receptor (BCR)-mediated in vitro proliferative responses, even at limiting amounts of stimulant [3].
• On the contrary, cells that overexpress Bcl-xL and Aiolos are unable to block apoptosis in the absence of IL-4 [4].
• IL-4 does not promote translocation of Aiolos or Bcl-xL, but induces tyrosine phosphorylation of Aiolos, which is required for dissociation from Bcl-xL [4].

Anatomical context of Ikzf3

• These studies support a model by which the high affinity plasma cell population in the BM undergoes a unique differentiation program that is dependent on Aiolos [5].
• Aiolos is required for the generation of high affinity bone marrow plasma cells responsible for long-term immunity [5].
• Northern blot analysis of various human tissues revealed that the Aiolos transcripts are expressed most strongly in peripheral blood leukocytes, the spleen, and the thymus, supporting the notion that Aiolos plays an important role in lymphoid lineages [6].
• Aiolos transcription factor controls cell death in T cells by regulating Bcl-2 expression and its cellular localization [7].

Physical interactions of Ikzf3

• We also identified functional Aiolos-binding sites in the Bcl-2 promoter, which are able to activate the luciferase reporter gene [7].

Regulatory relationships of Ikzf3

• Indirect immunofluorescence shows that IL-2 controls the cellular distribution of Aiolos and induces its tyrosine phosphorylation, required for dissociation from Ras [7].

Other interactions of Ikzf3

• Genetic mapping and allelic loss analysis in mouse thymic lymphomas of Helios and Aiolos belonging to the Ikaros gene family [1].
• Unexpectedly, B cell development at the immature B cell stage is severely impaired in the bone marrow of Aiolos/OBF-1 double-deficient mice, demonstrating the key role of these factors in the transition from pre-B to immature B cells [8].
• We propose a model for the regulation of Bcl-2 expression via Aiolos [7].
• We searched for proteins that interact with Ras in interleukin (IL)-2-stimulated or IL-2-deprived cells, and found that the transcription factor Aiolos interacts with Ras [7].

Analytical, diagnostic and therapeutic context of Ikzf3

• Failure to generate high affinity plasma cells in the BM and to sustain serum antibody titers is apparent after both primary and secondary immunization of Aiolos(-)(/)(-) mice with a range of hapten concentrations [5].
• Using yeast two-hybrid system, coimmunoprecipitation, and indirect immunofluorescence techniques, we found that Bcl-xL interacts with the transcription factor Aiolos in IL-4-stimulated cells, increasing upon IL-4 deprivation [4].
• Fluorescence in situ hybridization using a BAC clone established that the Aiolos gene is mapped to human chromosome band 17q11.2 [6].
• Gene targeting studies in mice have shown that the transcription factor Ikaros plays an essential role in lymphoid development and as a tumor suppressor in T cells, whereas the related gene Aiolos functions as a tumor suppressor in B cells [9].

References