An activating intragenic deletion in NOTCH1 in human T-ALL

J. Erika Haydu, Kim De Keersmaecker, Mary Kaye Duff, Elisabeth Paietta, Janis Racevskis, Peter H. Wiernik, Jacob M. Rowe, Adolfo Ferrando

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Oncogenic activating mutations in NOTCH1 occur in more than 50% of T-cell acute lymphoblastic leukemias (T-ALLs). In the present study, we describe a novel mechanism of NOTCH1 activation in T-ALL in which a deletion removing the 5′ portion of NOTCH1 abolishes the negative regulatory control of the extracellular domain and leads to constitutively active NOTCH1 signaling. Polypeptides translated from truncated transcripts encoded by the NOTCH1 deletion allele retain the transmembrane domain of the receptor and are constitutively cleaved by the γ-secretase complex, resulting in high levels of NOTCH1 signaling that can be effectively blocked by γ-secretase inhibitors. Our results expand the spectrum of oncogenic lesions activating NOTCH1 signaling in human T-ALL.

Original languageEnglish (US)
Pages (from-to)5211-5214
Number of pages4
Issue number22
StatePublished - Jun 5 2012

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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