Title: Novel roles of NOTCH and JAK3 during normal and malignant hematopoiesis
Description: A strict balance between the actions of cell-intrinsic and cell-extrinsic factors tightly controls hematopoietic development and homeostasis. We have studied the pleiotropic role of these cell-autonomous and cell non-autonomous contributions in normal and malignant hematopoiesis, with a focus on T cell and megakaryocyte development. We first tested the role of a human activating JAK3 mutation, found in patients with acute megakaryoblastic leukemia, during murine hematopoiesis using a bone marrow transplantation assay. We observed that JAK3 plays an important role in normal T cell development and showed that constitutive activation of this kinase leads to the development of cutaneous T cell lymphoma (CTCL) in mice, with a phenotype highly resembling human CTCL. In an attempt to understand the interplay between JAK3 and a known important regulator of T cell development, Notch, we also discovered that the Notch pathway is an important positive regulator of megakaryocyte development. We showed that activation of the Notch signaling pathway in hematopoietic stem and progenitor cells favors megakaryocyte development in vitro and in vivo, while inhibition of this pathway blocks this process.

To uncover the mechanism of Notch-induced megakaryocyte development, we tested the importance of the PI3-kinase/AKT pathway, which has recently been shown to cross-talk with Notch signaling, in other cellular contexts. Our findings demonstrate that the PI3K pathway is a crucial mediator of Notch-induced megakaryopoiesis, in that it is activated in hematopoietic progenitors upon Notch signaling and its over-activation or inhibition modulates megakaryocyte development induced by Notch signaling. Taken together, our results have uncovered the importance of JAK3-mediated signals in human T cell malignancies, derived from their importance during normal lymphopoiesis. Furthermore, we have identified a novel role for Notch as a positive regulator of megakaryocyte development, in addition to its known function in T cell development. Our findings underscore the complexity and plasticity of the hematopoietic system, and the pleiotropic nature of the factors involved in hematopoietic development and function.