Synergistic antileukemic therapies in NOTCH1-induced T-ALL

Marta Sanchez-Martin, Alberto Ambesi-Impiombato, Yue Qin, Daniel Herranz, Mukesh Bansal, Tiziana Girardi, Elisabeth Paietta, Martin S. Tallman, Jacob M. Rowe, Kim De Keersmaecker, Andrea Califano, Adolfo A. Ferrando

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2006-2011
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number8
DOIs
StatePublished - Feb 21 2017

Keywords

  • Leukemia
  • NOTCH1
  • Protein translation
  • Synergy
  • T-ALL

ASJC Scopus subject areas

  • General

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    Sanchez-Martin, M., Ambesi-Impiombato, A., Qin, Y., Herranz, D., Bansal, M., Girardi, T., Paietta, E., Tallman, M. S., Rowe, J. M., De Keersmaecker, K., Califano, A., & Ferrando, A. A. (2017). Synergistic antileukemic therapies in NOTCH1-induced T-ALL. Proceedings of the National Academy of Sciences of the United States of America, 114(8), 2006-2011. https://doi.org/10.1073/pnas.1611831114