Activating Mutations of <i>NOTCH1</i> in Human T Cell Acute Lymphoblastic Leukemia
Andrew P. Weng(Brigham and Women's Hospital), Adolfo A. Ferrando(Brigham and Women's Hospital), Woojoong Lee(Brigham and Women's Hospital), John P. Morris(Brigham and Women's Hospital), Lewis B. Silverman(Brigham and Women's Hospital), Cheryll Sanchez-Irizarry(Brigham and Women's Hospital), Stephen C. Blacklow(Brigham and Women's Hospital), A. Thomas Look(Brigham and Women's Hospital), Jon C. Aster(Brigham and Women's Hospital)
Cited by 2,713
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.