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

Authors
Journal
Leukemia
0887-6924
Publisher
Nature Publishing Group
Publication Date
Volume
25
Issue
10
Identifiers
DOI: 10.1038/leu.2011.130
Keywords
  • Article
Disciplines
  • Medicine

Abstract

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 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 HD class I, NOTCH1 HD class II and NOTCH1 JME alleles characterized by increased and aberrant S2 processing shows that both ADAM10, 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 either 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.

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