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

doi:10.1073/pnas.1611831114

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

Oncology

Research output: Contribution to journal › Article › peer-review

48 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 language	English (US)
Pages (from-to)	2006-2011
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	114
Issue number	8
DOIs	https://doi.org/10.1073/pnas.1611831114
State	Published - Feb 21 2017

Keywords

Leukemia
NOTCH1
Protein translation
Synergy
T-ALL

ASJC Scopus subject areas

General

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10.1073/pnas.1611831114

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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

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

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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.",

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AU - Bansal, Mukesh

AU - Girardi, Tiziana

AU - Paietta, Elisabeth

AU - Tallman, Martin S.

AU - Rowe, Jacob M.

AU - De Keersmaecker, Kim

AU - Califano, Andrea

AU - Ferrando, Adolfo A.

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AB - 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.

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KW - Synergy

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Synergistic antileukemic therapies in NOTCH1-induced T-ALL

Abstract

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