Brigham & Women's Hospital
Jon C. Aster, M.D., Ph.D.
Program Director
Brigham and Women's Hospital
20 Shattuck Street
Boston, MA, 02115
Mailstop: 612 Thorn Building
Phone: (617) 525-7329
Fax: (617) 264-5169
Email: jaster@rics.bwh.harvard.edu
The immediate goals of this program are to elucidate, how mutations in NOTCH1 receptors cause aberrant increases in signaling, and how these increases in signaling contribute to the pathogenesis of human T-cell acute lymhoblastic lymphoma/leukemia (T-ALL). Guided by these mechanistic insights, the long-term goal is to develop novel small molecule and antibody reagents that will afford new diagnostic and rationale therapeutic approaches in T-ALL and other malignancies associated with increased NOTCH signaling.
The components: 3 Integrated Projects, 2 Cores
Project 1 (Jon Aster, PI) will i), use cell-based assays to determine how mutations in the ectodomain and PEST domain of NOTCH1 cause increased production and stability of activated NOTCH1, respectively, and thereby synergize to increase NOTCH1 signals in human T-ALL cells; and ii), in collaboration with Dr. Pear, will determine the leukemogenicity of various NOTCH1 alleles in the mouse.
Project 2 (Warren Pear, PI) will use a variety of mouse models to determine the transforming ability of the recently identified Notch1 HD and/or PEST mutations, study the interaction of NOTCH1 with other proteins implicated in human T-ALL, and will identify critical target genes downstream of activated NOTCH1 that contribute to its leukemogenecity.
Project 3 (Stephen Blacklow, PI) will study the effects of mutations on the structure and stability of the purified heterodimerization domain, and determine the structure of the core NOTCH1 transcriptional activation complex.
The activities of this highly focused program will be supported by an administrative core (Core A, Jon Aster, Leader) and a Protein Production and Antibody Characterization Core (Core B, Stephen Blacklow, Leader).
The proposed studies and activities of this program will yield critical mechanistic insights into normal and leukemogenic NOTCH1 signaling, and produce valuable reagents for the scientific community as a whole, thereby creating new translational opportunities in cancers associated with altered NOTCH signaling.
