Interplay of Ikaros and Aiolos in controlling B lymphocytes

Transcription factor networks tightly regulate B lymphopoiesis, which equips the body with a diverse antibody repertoire and protects it against the invasion of pathogens. The development of antibody- secreting cells comprises many perilous steps that can lead to the production of self-reactive antibodies or malignant transformation at several B-cell stages. Ikaros and Aiolos, two related proteins of the same zinc-finger transcription factor family, play a crucial role in the regulation of B-lymphocyte proliferation and differentiation. Loss of function and deregulated expression have linked both factors to the development of leukemia and lymphomas. In particular, Ikaros has been found to be a major tumor suppressor involved in human B-cell acute lymphoblastic leukemia. Given the similarity of these proteins, Ikaros and Aiolos are thought to have the same function. It is broadly assumed that Ikaros family members can compensate for each others loss; hence, coexpression has been considered to contribute merely to a dosage effect. Results from recent studies, however, contradict the view of redundant functions shared by Ikaros and Aiolos and rather suggest differential roles during the same biological processes. In addition, my own preliminary data indicate non-redundant and even antagonistic functions of Ikaros and Aiolos during B-cell development. Here, I propose to study and compare the biological roles of Ikaros and Aiolos during late B-cell development. To gain insights into the role of both factors, we will study and compare the functionality of Ikaros-, Aiolos-, and double-deficient B cells. Transcription factors control gene expression by binding to DNA. To evaluate a synergistic or antagonistic action of Ikaros and Aiolos, we will compare the whole genome expression profiles of Ikaros-, Aiolos-, and double-deficient B cells. Last, I will study DNA occupancy of Ikaros and Aiolos and their interdependency on DNA-binding in B cells. I hypothesize that the affinity of Ikaros and Aiolos for DNA and their effector function is regulated independently and cell stage-specifically. Hence, the coexpression of the two factors allows for fine- tuning of gene expression during differentiation. My study will reveal new fundamental principles underlying the regulation of gene expression by members of transcription factor families. Additionally, elucidating the biological role of Ikaros and Aiolos, will help us to understand, how these factors regulate B cell differentiation and prevent the development of diseases. 1