title: An activating intragenic deletion in NOTCH1 in human T-ALL.
abstract: 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.
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
authors.forename: J Erika
authors.initials: JE
authors.lastname: Haydu
authors.forename: Kim
authors.initials: K
authors.lastname: De Keersmaecker
authors.forename: Mary Kaye
authors.initials: MK
authors.lastname: Duff
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.forename: Janis
authors.initials: J
authors.lastname: Racevskis
authors.forename: Peter H
authors.initials: PH
authors.lastname: Wiernik
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Rowe
authors.forename: Adolfo
authors.initials: A
authors.lastname: Ferrando
mesh_terms: D000328:Adult; D000483:Alleles; D005260:Female; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics*
chemical_list: C497761:NOTCH1 protein, human; D009363:Neoplasm Proteins; D051881:Receptor, Notch1