NOTCH1 extracellular juxtamembrane expansion mutations in T-ALL

Maria Luisa Sulis, Odette Williams, Teresa Palomero, Valeria Tosello, Sasikala Pallikuppam, Pedro J. Real, Kelly Barnes, Linda Zuurbier, Jules P. Meijerink, Adolfo A. Ferrando

Research output: Contribution to journalArticle

Abstract

Heterodimerization domain (HD) mutations in NOTCH1 induce ligand-independent activation of the receptor and contribute to the pathogenesis of one-third of human T-cell lymphoblastic leukemias (T-ALLs). Here we report a novel class of activating mutations in NOTCH1 leading to aberrant activation of NOTCH1 signaling in T-cell lymphoblasts. These so-called juxtamembrane expansion (JME) alleles consist of internal duplication insertions in the vicinity of exon 28 of the NOTCH1 gene encoding the extracellular juxtamembrane region of the receptor. Notably, structure-function analysis of leukemia-derived and synthetic JME mutants demonstrated that the aberrant activation of NOTCH1 signaling is dependent on the number of residues introduced in the extracellular juxtamembrane region of the receptor and not on the specific amino acid sequence of these insertions. JME NOTCH1 mutants are effectively blocked by γ-secretase inhibitors and require an intact metalloprotease cleavage site for activation. Overall, these results show a novel mechanism of NOTCH1 activation in T-ALL and provide further insight on the mechanisms that control the activation of NOTCH1 signaling.

Original languageEnglish
Pages (from-to)733-740
Number of pages8
JournalBlood
Volume112
Issue number3
DOIs
Publication statusPublished - Aug 1 2008

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Sulis, M. L., Williams, O., Palomero, T., Tosello, V., Pallikuppam, S., Real, P. J., Barnes, K., Zuurbier, L., Meijerink, J. P., & Ferrando, A. A. (2008). NOTCH1 extracellular juxtamembrane expansion mutations in T-ALL. Blood, 112(3), 733-740. https://doi.org/10.1182/blood-2007-12-130096