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

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Subcommittee G - Education (NCI)
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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
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