The human homologue of Notch1 was originally identified at the chromosomal breakpoint in a recurrent chromosomal translocation in T-cell leukemia. We have previously shown that constitutive expression of activated Notch1 causes T-cell leukemia in mice and that its role in leukemia may be related to its normal function in lymphoid development. As part of our long term plan to understand the role of Notch in leukemia, we have initiated studies to understand Notch function in hematopoiesis. Notch proteins are a conserved family that regulates cell fate choice in many lineages, including stem cells. Recently, we have provided evidence that Notch plays a key role in regulating lymphoid cell fate decisions from hematopoietic stem cells. To further understand this process, we have undertaken studies to understand Notch function in B cell development. Our preliminary results suggest that Notch signaling promotes apoptosis of B cells and that inhibition of Notch signaling leads to B cell development at the expense of T cell development, both in vivo and in organ cultures. The proposed studies focus on the role of Notch signaling in B cell development and survival.
In Aim 1, we will focus on a particular modulator of Notch signaling that antagonizes Notch signaling and promotes B cell development from hematopoietic stem cells. The studies in this aim will use a combination of in vivo, organ culture, and in vitro methods to understand the function of this protein in B cell development.
In Specific Aim 2, we will characterize Notch signaling in B lymphoid subsets and determine the mechanism by which Notch signaling specifically promotes B cell death. These studies will lead to an improved understanding of lymphoid development and function, and in doing so, will provide therapeutic insights into treating leukemia and other diseases of the immune and hematopoietic systems.
