Our long term goal is to understand the role of dysregulated Notch signaling in the pathogenesis of T cell leukemia and to develop new diagnostic, prognostic, and therapeutic strategies based on this information. Recently, Notch mutations have been associated with more than half of human T-ALL, suggesting that advances in understanding leukemogenic Notch signaling will have a significant impact on this disease. Over the last decade, we have developed mouse models, tissue culture assays, and biochemical methods to investigate the role of Notch signaling in T cell leukemia. Here, we will build on these findings to determine whether mutant forms of Notchl drive ectopic T cell development and induce leukemias in mice, and will correlate these outcomes with primary effects of various Notchl alleles on defined subsets of hematopoietic progenitors. Notchl appears to have a broad capacity to collaborate with a number of other transcription factors linked to human T-ALL development. We will determine the ability of these mutated Notch alleles to synergize with other genes commonly implicated in human T-ALL, such as Hox 11, Hox11L and Tall. Finally, Notchl's leukemogenic activity has been linked to up-regulation of unknown downstream target genes. Using a series of well-controlled expression profiling experiments and novel Notch-dependent T-ALL cell lines, we will identify downstream target genes that contribute to the sustained growth of T-ALL cells. Together, these studies will provide a deeper understanding of the pathogenesis of Notch-induced leukemia, and thereby move us closer to novel therapeutic interventions in this disease and other pathologic states characterized by aberrant Notch signaling.
The specific aims of this proposal are: 1. To determine the transforming ability of the recently identified Notchl HD and/or PEST mutations 2. To determine how Notchl signals of varying strength interact with other transcription factors to induce TALL 3. To determine the mechanism(s) by which oncogenic Notchl promotes transformation

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA119070-04
Application #
7874671
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
4
Fiscal Year
2009
Total Cost
$414,809
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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
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
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
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

Showing the most recent 10 out of 61 publications