Redundancy and specificity of the metalloprotease system mediating oncogenic NOTCH1 activation in T-ALL

Leukemia. 2011 Oct;25(10):1564-9. doi: 10.1038/leu.2011.130. Epub 2011 May 31.


Oncogenic mutations in NOTCH1 are present in over 50% of T-cell lymphoblastic leukemias (T-ALLs). Activation of NOTCH1 requires a double proteolytic processing in the extracellular region of the receptor (S2) and in the transmembrane domain (S3). Currently, anti-NOTCH1 therapies based on the inhibition of S3 processing via small molecule γ-secretase inhibitors are in development. Here we report on the characterization of the protease system responsible for S2 processing of NOTCH1 in T-ALL. Analysis of NOTCH1 heterodimerization (HD) class I, NOTCH1 HD class II and NOTCH1 JME alleles characterized by increased and aberrant S2 processing shows that both ADAM10 (a disintegrin and metalloprotease 10), a metalloprotease previously implicated in activation of wild-type NOTCH1 in mammalian cells, and ADAM17, a closely related protease capable of processing NOTCH1 in vitro, contribute to the activation of oncogenic forms of NOTCH1. However, and despite this apparent functional redundancy, inhibition of ADAM10 is sufficient to blunt NOTCH1 signaling in T-ALL lymphoblasts. These results provide further insight on the mechanisms that control the activation of oncogenic NOTCH1 mutants and identify ADAM10 as potential therapeutic target for the inhibition of oncogenic NOTCH1 in T-ALL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / antagonists & inhibitors
  • ADAM Proteins / metabolism*
  • ADAM10 Protein
  • Alleles
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / metabolism*
  • Base Sequence
  • DNA Primers
  • Dimerization
  • Humans
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / metabolism*
  • Oncogenes*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / enzymology*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • RNA Interference
  • Real-Time Polymerase Chain Reaction
  • Receptor, Notch1 / metabolism*
  • Substrate Specificity


  • DNA Primers
  • Membrane Proteins
  • NOTCH1 protein, human
  • Receptor, Notch1
  • Amyloid Precursor Protein Secretases
  • ADAM Proteins
  • ADAM10 Protein
  • ADAM10 protein, human