An activating intragenic deletion in NOTCH1 in human T-ALL

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

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5211-5214
Number of pages4
JournalBlood
Volume119
Issue number22
DOIs
StatePublished - Jun 5 2012

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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
T-cells
Amyloid Precursor Protein Secretases
Chemical activation
Alleles
Peptides
Mutation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Haydu, J. E., De Keersmaecker, K., Duff, M. K., Paietta, E. M., Racevskis, J., Wiernik, P. H., ... Ferrando, A. (2012). An activating intragenic deletion in NOTCH1 in human T-ALL. Blood, 119(22), 5211-5214. https://doi.org/10.1182/blood-2011-10-388504

An activating intragenic deletion in NOTCH1 in human T-ALL. / Haydu, J. Erika; De Keersmaecker, Kim; Duff, Mary Kaye; Paietta, Elisabeth M.; Racevskis, Janis; Wiernik, Peter H.; Rowe, Jacob M.; Ferrando, Adolfo.

In: Blood, Vol. 119, No. 22, 05.06.2012, p. 5211-5214.

Research output: Contribution to journalArticle

Haydu, JE, De Keersmaecker, K, Duff, MK, Paietta, EM, Racevskis, J, Wiernik, PH, Rowe, JM & Ferrando, A 2012, 'An activating intragenic deletion in NOTCH1 in human T-ALL', Blood, vol. 119, no. 22, pp. 5211-5214. https://doi.org/10.1182/blood-2011-10-388504
Haydu JE, De Keersmaecker K, Duff MK, Paietta EM, Racevskis J, Wiernik PH et al. An activating intragenic deletion in NOTCH1 in human T-ALL. Blood. 2012 Jun 5;119(22):5211-5214. https://doi.org/10.1182/blood-2011-10-388504
Haydu, J. Erika ; De Keersmaecker, Kim ; Duff, Mary Kaye ; Paietta, Elisabeth M. ; Racevskis, Janis ; Wiernik, Peter H. ; Rowe, Jacob M. ; Ferrando, Adolfo. / An activating intragenic deletion in NOTCH1 in human T-ALL. In: Blood. 2012 ; Vol. 119, No. 22. pp. 5211-5214.
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