DOI: 10.1126/science.1102160 ISSN:

Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia

Andrew P. Weng, Adolfo A. Ferrando, Woojoong Lee, John P. Morris, Lewis B. Silverman, Cheryll Sanchez-Irizarry, Stephen C. Blacklow, A. Thomas Look, Jon C. Aster
  • Multidisciplinary

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.

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