期刊
LEUKEMIA
卷 31, 期 10, 页码 2037-2047出版社
SPRINGERNATURE
DOI: 10.1038/leu.2017.10
关键词
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资金
- Fund for Scientific Research Flanders ('FWO Vlaanderen') [GA00113N, 3G065614, G.0C47.13N, 31500615W, G.0529.12N, G.0817.13N]
- Children Cancer Fund Ghent
- Belgian Foundation Against Cancer [365W3415W, B/13590]
- Belgian Stand Up To Cancer Foundation [365Y9115W]
- agency for Innovation by Science and Technology ('IWT') [111528]
- Geconcerteerde Onderzoeksacties Ghent University [GOA-01GB1013W]
- Cancer League of the Canton of Zurich
- Empiris Foundation
- Kinderkrebsforschung Schweiz
- Sassella Foundation
- Stiftung fur Krebsbekampfung
- Swiss National Science Foundation [310030-133108]
- Fondation Panacee
- University of Zurich
- Ghent University
- Hercules Foundation
- Flemish Government-Department EWI
- Swiss National Science Foundation (SNF) [310030_133108] Funding Source: Swiss National Science Foundation (SNF)
Inhibition of anti-apoptotic BCL-2 (B-cell lymphoma 2) has recently emerged as a promising new therapeutic strategy for the treatment of a variety of human cancers, including leukemia. Here, we used T-cell acute lymphoblastic leukemia (T-ALL) as a model system to identify novel synergistic drug combinations with the BH3 mimetic venetoclax (ABT-199). In vitro drug screening in primary leukemia specimens that were derived from patients with high risk of relapse or relapse and cell lines revealed synergistic activity between venetoclax and the BET (bromodomain and extraterminal) bromodomain inhibitor JQ1. Notably, this drug synergism was confirmed in vivo using T-ALL cell line and patient-derived xenograft models. Moreover, the therapeutic benefit of this drug combination might, at least in part, be mediated by an acute induction of the pro-apoptotic factor BCL2L11 and concomitant reduction of BCL-2 upon BET bromodomain inhibition, ultimately resulting in an enhanced binding of BIM (encoded by BCL2L11) to BCL-2. Altogether, our work provides a rationale to develop a new type of targeted combination therapy for selected subgroups of high-risk leukemia patients.
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