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Jon C. Aster, MD, PhD

Professor, Department of Pathology, Harvard Medical School

Associate Pathologist, Pathology, Brigham And Women's Hospital

Contact Info

Jon Aster
Brigham And Women's Hospital
20 Shattuck Street
Boston, MA, 02115
Mailstop: 612 Thorn Building
Phone: 617-525-4406
jaster@partners.org

Assistant

Muriel Goutas
Administrative Assistant
Pathology
Brigham And Women's Hospital
20 Shattuck Street
Boston, MA, 02115
Phone: 617-525-4370
Fax: 617-264-5169
mgoutas@partners.org

DF/HCC Program Affiliation

Lymphoma and Myeloma, Co-Leader
Leukemia

DF/HCC Associations

Member, Clinical Science Coordinating Committee
Director, Specialized HistoPathology - Longwood
Co-Chair, Membership Committee
Deputy Associate Director, Membership, Executive Committee
Institutional Representative for BWH, Membership Committee
Member, Center Scientific Council

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.

Publications

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