Disrupted eosinophil homeostasis in Ikaros-mutant mice 4769

Abstract Description Ikaros is a transcription factor encoded by the Ikzf1 gene, known to be a critical regulator of immune cell development. Ikaros regulates multiple immune cell types, and is found to regulate multiple stages of development within one lineage. The importance of Ikaros to human health is underscored by recurrent IKZF1 mutations found in patients with immunodeficiency, autoimmunity, and leukemia. IKZF1 mutations are also reported in patients with eosinophilia, a condition with elevated levels of eosinophils. However, a role for Ikaros in regulation of eosinophils has not yet been described or experimentally tested. We have found increased levels of eosinophils in the bone marrow of two Ikzf1-mutant mouse models. Furthermore, we have found that these two mouse models display different phenotypes in regards to eosinophils in peripheral tissues, suggesting that Ikaros regulates two or more aspects of eosinophil biology. We study the role of Ikaros in regulation of eosinophil homeostasis through analysis of these Ikzf1-mutant mouse models as well as by using Ikaros-perturbation in human cells. We have found that Ikzf1-mutant bone marrow cells have different response to cytokine-driven in vitro differentiation. Furthermore, degradation of Ikaros, and the family member Aiolos, by IMiDs leads to altered expression of chemokine receptors, which are important for migration. We conclude that Ikaros is an important regulator of eosinophils, and aim to uncover the underlying mechanisms. Topic Categories Hematopoiesis and Immune System Development (HEM)