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

Synergistic antileukemic therapies in NOTCH1-induced T-ALL.

Author information

1
Institute for Cancer Genetics, Columbia University, New York, NY 10032.
2
Department of Systems Biology, Columbia University, New York, NY 10032.
3
KU Leuven, University of Leuven, 3000 Leuven, Belgium.
4
Department of Oncology, Leuven Cancer Institute, 3000 Leuven, Belgium.
5
Montefiore Medical Center, New York, NY 10467.
6
Department of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
7
Technion, Israel Institute of Technology, Haifa 3200003, Israel.
8
Institute for Cancer Genetics, Columbia University, New York, NY 10032; af2196@columbia.edu.
9
Department of Pediatrics, Columbia University, New York, NY 10032.
10
Department of Pathology, Columbia University, New York, NY 10032.

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.

KEYWORDS:

NOTCH1; T-ALL; leukemia; protein translation; synergy

PMID:
28174276
PMCID:
PMC5338362
DOI:
10.1073/pnas.1611831114
[Indexed for MEDLINE]
Free PMC Article

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