Mutant nucleophosmin deregulates cell death and myeloid differentiation through excessive caspase-6 and -8 inhibition

Blood. 2010 Oct 28;116(17):3286-96. doi: 10.1182/blood-2009-12-256149. Epub 2010 Jul 6.

Abstract

In up to one-third of patients with acute myeloid leukemia, a C-terminal frame-shift mutation results in abnormal and abundant cytoplasmic accumulation of the usually nucleoli-bound protein nucleophosmin (NPM), and this is thought to function in cancer pathogenesis. Here, we demonstrate a gain-of-function role for cytoplasmic NPM in the inhibition of caspase signaling. The NPM mutant specifically inhibits the activities of the cell-death proteases, caspase-6 and -8, through direct interaction with their cleaved, active forms, but not the immature procaspases. The cytoplasmic NPM mutant not only affords protection from death ligand-induced cell death but also suppresses caspase-6/-8-mediated myeloid differentiation. Our data hence provide a potential explanation for the myeloid-specific involvement of cytoplasmic NPM in the leukemogenesis of a large subset of acute myeloid leukemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Caspase 6 / metabolism
  • Caspase 8 / metabolism
  • Caspase Inhibitors*
  • Cell Differentiation
  • Cell Line
  • Cytoplasm / metabolism
  • HeLa Cells
  • Humans
  • Mutation*
  • Myeloid Cells / cytology*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • Nucleophosmin
  • Up-Regulation

Substances

  • Caspase Inhibitors
  • NPM1 protein, human
  • Nuclear Proteins
  • Nucleophosmin
  • Caspase 6
  • Caspase 8