Abstract
Both Ikaros and Notch are transcriptional regulators that are essential for normal T cell development. Cooperative mutations causing a reduction in Ikaros activity and an increase in Notch activation have been hypothesized to promote T cell leukemia. However, it is not known whether Notch deregulation plays a preferential or obligatory role in the leukemias that arise in Ikaros null (Ik-/-) mice with 100% penetrance. In order to answer this question, we abrogated Notch target gene activation in Ik-/- thymocytes using conditional inactivation of the DNA-binding Notch-target gene activator RBP-J. Through analyses of these mice we have made two important discoveries.
First, thymocytes that lack either Ikaros alone or both Ikaros and RBP-J exhibit high level derepression of Notch target genes. However, this derepression is not observed in thymocytes lacking RBP-J alone, which suggests that Ikaros, but not RBP-J, is required for Notch target gene repression in DP thymocytes. This data represents a major shift in our understanding of regulatory factors involved in Notch target gene repression. Secondly, Ik-/- mice develop clonal T cell populations, a hallmark of leukemia, with similar kinetics in the presence or absence of RBP-J. The appearance of clonal populations in the thymus and spleen of Ik-/- mice lacking RBP-J indicates that T cell transformation in the absence of Ikaros does not require deregulated Notch signaling.
