Synergistic antileukemic therapies in NOTCH1-induced T-ALL

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

Research output: Contribution to journalArticle

10 Citations (Scopus)

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

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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Protein Biosynthesis
Amyloid Precursor Protein Secretases
Therapeutics
Phosphorylation
Clinical Trials
Pharmaceutical Preparations
Genes
withaferin A

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Sanchez-Martin, M., Ambesi-Impiombato, A., Qin, Y., Herranz, D., Bansal, M., Girardi, T., ... 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

Synergistic antileukemic therapies in NOTCH1-induced T-ALL. / Sanchez-Martin, Marta; Ambesi-Impiombato, Alberto; Qin, Yue; Herranz, Daniel; Bansal, Mukesh; Girardi, Tiziana; Paietta, Elisabeth M.; Tallman, Martin S.; Rowe, Jacob M.; De Keersmaecker, Kim; Califano, Andrea; Ferrando, Adolfo A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 8, 21.02.2017, p. 2006-2011.

Research output: Contribution to journalArticle

Sanchez-Martin, M, Ambesi-Impiombato, A, Qin, Y, Herranz, D, Bansal, M, Girardi, T, Paietta, EM, Tallman, MS, Rowe, JM, De Keersmaecker, K, Califano, A & Ferrando, AA 2017, 'Synergistic antileukemic therapies in NOTCH1-induced T-ALL', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 8, pp. 2006-2011. https://doi.org/10.1073/pnas.1611831114
Sanchez-Martin M, Ambesi-Impiombato A, Qin Y, Herranz D, Bansal M, Girardi T et al. Synergistic antileukemic therapies in NOTCH1-induced T-ALL. Proceedings of the National Academy of Sciences of the United States of America. 2017 Feb 21;114(8):2006-2011. https://doi.org/10.1073/pnas.1611831114
Sanchez-Martin, Marta ; Ambesi-Impiombato, Alberto ; Qin, Yue ; Herranz, Daniel ; Bansal, Mukesh ; Girardi, Tiziana ; Paietta, Elisabeth M. ; Tallman, Martin S. ; Rowe, Jacob M. ; De Keersmaecker, Kim ; Califano, Andrea ; Ferrando, Adolfo A. / Synergistic antileukemic therapies in NOTCH1-induced T-ALL. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 8. pp. 2006-2011.
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