Research Abstract

My lab is focused on understanding the pathogenesis of Notch1-induced T-cell acute lymphoblastic leukemia/lymphoma (T-ALL). Notch1 (N1) is a member of a family of structurally-unique single-pass transmembrane receptors that regulate cellular differentiation through a novel type of signal transduction pathway. Normal N1 activation is triggered by ligand-dependent proteolytic cleavages that result in the release of the intracellular portion of N1 (ICN1), which then translocates to the nucleus and forms a transcription activation complex with the DNA-binding factor RBP-Jk/CSL and co-activators of the mastermind family. In 2004, we discovered frequent "gain-of-function" point mutations involving NOTCH1 in T-ALLs lacking the t(7;9). These mutations, depending on their location, either increase the rate of proteolysis and generation of ICN1, or enhance the stability of ICN1. ICN1 turns on a number of downstream targets, including c-Myc and components of the mTOR pathway, that support the growth and proliferation of T-ALL cells. Current activities include studies aimed at understanding in detail how Notch1 mutations act to increase ICN1 production and stability; the nature of the cross-talk between Notch1, mTOR, and other pathways that regulate cellular metabolism; the development of novel inhibitors that are selective for Notch1; and the identification and application of small molecules that act synergistically with Notch pathway inhibitors against tumor cells that depend on Notch signals.