Synergistic antileukemic therapies in NOTCH1-induced T-ALL

Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):2006-2011. doi: 10.1073/pnas.1611831114. Epub 2017 Feb 7.


The Notch1 gene is a major oncogenic driver and therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL). However, inhibition of NOTCH signaling with γ-secretase inhibitors (GSIs) has shown limited antileukemic activity in clinical trials. Here we performed an expression-based virtual screening to identify highly active antileukemic drugs that synergize with NOTCH1 inhibition in T-ALL. Among these, withaferin A demonstrated the strongest cytotoxic and GSI-synergistic antileukemic effects in vitro and in vivo. Mechanistically, network perturbation analyses showed eIF2A-phosphorylation-mediated inhibition of protein translation as a critical mediator of the antileukemic effects of withaferin A and its interaction with NOTCH1 inhibition. Overall, these results support a role for anti-NOTCH1 therapies and protein translation inhibitor combinations in the treatment of T-ALL.

Keywords: NOTCH1; T-ALL; leukemia; protein translation; synergy.

Publication types

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

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Gene Expression Profiling
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Targeted Therapy / methods
  • Phosphorylation / drug effects
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Protein Biosynthesis / drug effects*
  • Receptor, Notch1 / antagonists & inhibitors*
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • Signal Transduction / drug effects
  • Withanolides / pharmacology
  • Xenograft Model Antitumor Assays
  • eIF-2 Kinase / metabolism


  • Enzyme Inhibitors
  • NOTCH1 protein, human
  • Receptor, Notch1
  • Withanolides
  • eIF-2 Kinase
  • Amyloid Precursor Protein Secretases
  • withaferin A