The overarching goal of this program is to elucidate fundamental properties of Notch signaling that are central to the pathogenesis of cancer. The Notch pathway is one of perhaps 15 or so signaling pathways that regulate development and tissue homeostasis in metazoan animals and which are frequently deranged in human diseases, including cancer. The clearest example of an oncogenic role for Notch is in T cell acute lymphoblastic leukemia/lymphoma (T-ALL), in which gain-of-function Notchl mutations are common. Notchl is a compelling rational therapeutic target in T-ALL, but attempts to treat T-ALL patients with Notch inhibitors to date have been unsuccessful. Thus, it is apparent that more basic and translational research is needed if Notch-directed therapies are to be effective. With this need in mind, Projects 1 and 2 of this Program have complementary aims focused on filling critical gaps in our basic understanding of how Notchl activates its target genes, which are ultimately responsible for driving T-ALL cell growth and survival. The specific overall objectives of Project 1 and Project 2 are: 1. To determine how Notchl regulates the genomes of T-ALL cells 2. To determine how Notchl regulates the genomes of normal thymocytes The mutations in Notchl that lead to T-ALL often result in ligand-independent proteolysis and receptor activation, but such mutations are rare to non-existent in other cancers. On the other hand, there is abundant evidence that ligand-mediated Notch receptor activation has important roles in cancer, both within tumor cell populations and benign stromal elements, such as endothelial cells and immune cells. Thus, understanding how ligands activate Notch receptors has broad cancer relevance, yet many basic aspects of the events underlying ligand-mediated Notch activation remain unknown. Project 3 will address major gaps in current knowledge by pursuing the following objectives: 3. To test the hypothesis that mechanical force is responsible for Notch receptor activation 4. To understand the molecular """"""""logic"""""""" of ligand endocytosis, an event that is essential for activation of Notch receptors by ligands The goals of the program will be reached in part with the support of a new Bioinformatics Core (Core B) led by Dr. Shirley Liu, an investigator with a strong background in informatics approaches to understanding cancer epigenetics.

Public Health Relevance

The cohesive, highly interactive nature of our Program and the rich research environments of its host institutions will support the achievement of these objectives, which promise to address important questions of broad relevance to cancer and other diseases in which Notch signaling has been implicated. By meeting these objectives Program will drive conceptual and molecular advances needed for more precise and effective targeting of the Notch pathway in a variety of human maladies, including cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1)
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Mufson, R Allan
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Brigham and Women's Hospital
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Johnson, John L; Georgakilas, Georgios; Petrovic, Jelena et al. (2018) Lineage-Determining Transcription Factor TCF-1 Initiates the Epigenetic Identity of T Cells. Immunity 48:243-257.e10
Jiang, Peng; Lee, Winston; Li, Xujuan et al. (2018) Genome-Scale Signatures of Gene Interaction from Compound Screens Predict Clinical Efficacy of Targeted Cancer Therapies. Cell Syst 6:343-354.e5
Severson, Eric; Arnett, Kelly L; Wang, Hongfang et al. (2017) Genome-wide identification and characterization of Notch transcription complex-binding sequence-paired sites in leukemia cells. Sci Signal 10:
Ryan, Russell J H; Petrovic, Jelena; Rausch, Dylan M et al. (2017) A B Cell Regulome Links Notch to Downstream Oncogenic Pathways in Small B Cell Lymphomas. Cell Rep 21:784-797
McMillan, Brian J; Tibbe, Christine; Drabek, Andrew A et al. (2017) Structural Basis for Regulation of ESCRT-III Complexes by Lgd. Cell Rep 19:1750-1757
Pajcini, Kostandin V; Xu, Lanwei; Shao, Lijian et al. (2017) MAFB enhances oncogenic Notch signaling in T cell acute lymphoblastic leukemia. Sci Signal 10:
Sajed, Dipti P; Faquin, William C; Carey, Chris et al. (2017) Diffuse Staining for Activated NOTCH1 Correlates With NOTCH1 Mutation Status and Is Associated With Worse Outcome in Adenoid Cystic Carcinoma. Am J Surg Pathol 41:1473-1482
Aster, Jon C; Pear, Warren S; Blacklow, Stephen C (2017) The Varied Roles of Notch in Cancer. Annu Rev Pathol 12:245-275
Seegar, Tom C M; Killingsworth, Lauren B; Saha, Nayanendu et al. (2017) Structural Basis for Regulated Proteolysis by the ?-Secretase ADAM10. Cell 171:1638-1648.e7
Chiang, Mark Y; Wang, Qing; Gormley, Anna C et al. (2016) High selective pressure for Notch1 mutations that induce Myc in T-cell acute lymphoblastic leukemia. Blood 128:2229-2240

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