Project 1 Title: The role of Notch Ligands in expansion of fetal liver hematopoietic stem cells (HSC). We have previously shown that the Notch receptor is critical for the proliferation and function of fetal HSCs (Gerhardt and Pajcini, Genes and Development 2014). One key question arose from these studies: If the Notch receptor is expressed on the stem cells, what is the cell that is presenting the ligand that turns on Notch signaling. Since Notch signaling is a cell-contact mediated event, the project will involve determination of the ligand and cell type that initiates the signaling event in the stem cells. We have the means to use conditional genetic mouse models and fetal liver cellular analysis by flow cytometry to determine the ligand and cell type that influence the expansion and function of HSCs. This is critical in understanding how blood is generated in during development and how expansion of stem cells can be achieved later in adult life.
– The role of Notch Ligands in expansion of fetal liver hematopoietic stem cells (HSC).
Project 2 Title: Enhancing the function of E3 ubiquitin ligase Deltex1 in Notch-driven T-cell acute lymphoblastic leukemia. Gain-of-function driving mutations are present in over 60% of all childhood T-cell leukemia. Targeting Notch signaling has been shown to be effective in limiting tumor burden, however given the systemic nature of leukemia, a broad inhibition of Notch signaling is too toxic and presents with severe intestinal side-effects to the patient. Thus, leukemia specific treatments are required. We have performed several screens to identify unique oncogenic features of Notch signaling. In a cDNA screen, we identified MafB as a transcriptional co-activator of leukemic T-cell genes (See attached publication). We have recently performed mass spectroscopy in combination with RNA sequencing to identify Notch interacting proteins and transcriptional targets. Deltex1 is the top hit in this category and the focus of the project will be to determine the role of Deltex1 in oncogenic Notch signaling and how it can be used to specifically target leukemic T-cells without systemic side effects.
– Enhancing the function of E3 ubiquitin ligase Deltex1 in Notch-driven T-cell acute lymphoblastic leukemia.