Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia

  • Science. 2004 Oct 8;306(5694):269-71. doi: 10.1126/science.1102160.
Andrew P Weng  1 ,  Adolfo A Ferrando ,  Woojoong Lee ,  John P Morris 4th ,  Lewis B Silverman ,  Cheryll Sanchez-Irizarry ,  Stephen C Blacklow ,  A Thomas Look ,  Jon C Aster
Affiliations
  • 1. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
PMID: 15472075 DOI: 10.1126/science.1102160
Abstract

Very rare cases of human T cell Acute Lymphoblastic Leukemia (T-ALL) harbor chromosomal translocations that involve NOTCH1, a gene encoding a transmembrane receptor that regulates normal T cell development. Here, we report that more than 50% of human T-ALLs, including Tumors from all major molecular oncogenic subtypes, have activating mutations that involve the extracellular heterodimerization domain and/or the C-terminal PEST domain of NOTCH1. These findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with Notch signaling.