Notch signaling plays an important role in diverse cellular and developmental processes, including differentiation, proliferation, survival, and apoptosis. For instance, the mammalian NOTCH1 gene plays an essential role in the development of T cells from common lymphoid progenitors, and enforced NOTCH1 signaling leads to T cell differentiation at the expense of B cell differentiation. Recent findings have identified an opposing role for Deltex, a known genetic modifier of Notch signaling in Drosophila, in lymphoid fate determination in which enforced Deltex expression favors B cell development at the expense of T cell development. The current literature supports a model in which Notch signals are exquisitely regulated temporally and spatially at multiple levels to achieve normal lymphoid development. When dysregulated, however, Notch signaling has been implicated in neoplastic transformation. In fact, mammalian NOTCH1 was initially identified as a chromosomal translocation breakpoint partner in sporadic human pre-T acute lymphoblastic leukemias (T-ALL) harboring a recurrent t(7;9)(q34;q34.3), which leads to the production of constitutively active forms of Notch. Investigation into the molecular mechanisms which underlie lymphoid lineage commitment and neoplastic transformation are essential if progress is to be made in the development of novel therapeutic strategies. The broad goals of this proposal are to elucidate the opposing roles that Notch and Deltex play in lymphoid development, to determine how dysregulation of the Notch signaling pathway leads to neoplastic transformation, and to identify potential molecular targets for therapeutic intervention. A unique combination of small molecule, polypeptide, and nucleic acid-based reagents will be employed to modulate various components of the Notch signaling pathway, and their effects assayed in both in vitro and in vivo/ex vivo model systems of normal development and tumorigenesis.
The specific aims of the proposal are 1) to define which Notch signaling events are important for T cell transformation, and 2) to define the mechanism by which Deltex promotes B cell fate. This proposal also outlines in detail a comprehensive career development plan that will provide essential training activities necessary to achieve the long-term scientific objectives as well as to facilitate the candidate's transition to independence. The most salient of these activities include technical training in the most recent molecular biology, protein biochemistry, and bioinformatics methodologies, with acquisition of critical skills in organ culture and in vivo models of development and tumorigenesis.
| Weng, Andrew P; Ferrando, Adolfo A; Lee, Woojoong et al. (2004) Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306:269-71 |
