DF/HCC Program Affiliation

Lymphoma and Myeloma, Co-Leader
Leukemia

DF/HCC Associations

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

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

• Gordon WR, Vardar-Ulu D, Histen G, Sanchez-Irizarry C, Aster JC, Blacklow SC.Structural basis for autoinhibition of Notch.Nat Struct Mol Biol 2007 Apr;14(4):295-300.
  17401372
• Shepard JL, Amatruda JF, Finkelstein D, Ziai J, Finley KR, Stern HM, Chiang K, Hersey C, Barut B, Freeman JL, Lee C, Glickman JN, Kutok JL, Aster JC, Zon LI.A mutation in separase causes genome instability and increased susceptibility to epithelial cancer
  17210788
• Chiang MY, Xu ML, Histen G, Shestova O, Roy M, Nam Y, Blacklow SC, Sacks DB, Pear WS, Aster JC.Identification of a Conserved Negative Regulatory Sequence That Influences the Leukemogenic Activity of NOTCH1.Mol Cell Biol 2006 Aug;26(16):6261-71.
  16880534
• Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C, Del Bianco C, Rodriguez CG, Sai H, Tobias J, Li Y, Wolfe MS, Shachaf C, Felsher D, Blacklow SC, Pear WS, Aster.c-Myc is an important direct target of Notch1 in T-cell acute lymphoblast
  16847353
• Sanchez-Irizarry C, Carpenter AC, Weng AP, Pear WS, Aster JC, Blacklow SC.Notch subunit heterodimerization and prevention of ligand-independent proteolytic activation depend, respectively, on a novel domain and the LNR repeats.Mol Cell Biol 2004 Nov;24(21
  15485896
• Weng AP, Ferrando AA, Lee W, Morris JP, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC.Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia.Science 2004 Oct 8;306(5694):269-71.
  15472075