CaNCURE Mentors

Jon C Aster, M.D., Ph.D.

Professor of Pathology
Harvard Medical School

Associate Pathologist
Brigham and Women's Hospital

Biography: Dr. Aster is an Associate Professor of Pathology at the Harvard Medical School. In addition to numerous publications, professional honors, and hospital appointments, Dr. Aster is a co-leader of the Cancer Research Center of the Brigham Biomedical Research Institute, Deputy Director for Membership of the Dana-Farber/Harvard Cancer Center, and leads a multi-institutional NCI-supported program on oncogenic Notch signaling. His laboratory conducts research on Notch, a fundamental signaling pathway that controls the way cells communicate with one another and respond to their external environment. This pathway plays a central role in regulating many aspects of normal cellular development. It is also important in certain forms of leukemia, most notably T-cell acute lymphoblastic leukemia (T-ALL). Newly made Notch receptors reside on the surface of the cell, but when activated by ligand proteins expressed on adjacent cells, part of the receptor moves to the nucleus where it activates gene expression. Notch is one of a handful of signaling pathways that permit cells to respond to cues from their environment. These instructive signals regulate normal behavior and often go awry in cancer and other diseases. Dr. Aster’s laboratory published a seminal paper in the journal Science in 2004 that described the discovery of mutations in the Notch1 receptor in T-ALL. These mutations increase Notch signaling and drive the growth of the leukemia cells. To date, this finding remains the best example of an abnormality in the Notch pathway that leads to a human cancer.

Research and Expertise: 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.



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