Journal
LEUKEMIA
Volume 28, Issue 6, Pages 1216-1226Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2013.366
Keywords
T-cell acute lymphoblastic leukemia; Notch1; proteasome inhibitor; Sp1; chemosensitization
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Funding
- High-Tech Research Center Project for Private Universities: Matching Fund Subsidy from MEXT
- JSPS
- Japan Leukemia Research Fund
- Takeda Science Foundation
- Naito Foundation
- Yasuda Medical Foundation
- Mitsui Life Social Welfare Foundation
- Uehara Memorial Foundation
- Grants-in-Aid for Scientific Research [23591405, 26461430, 23591549, 25461434, 25118721] Funding Source: KAKEN
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The Notch signaling pathway has been recognized as a key factor for the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL), because of the high incidence of activating mutations of Notch1. Notch inhibition could serve as a new treatment strategy for T-ALL; however, the attempts to perturb Notch signaling pathways have been unsuccessful so far. In this study, we found that proteasome inhibitors exert cytotoxic effects on T-ALL cells with constitutive activation of Notch1 to a similar extent as myeloma cells. The proteasome inhibitor bortezomib repressed the transcription of Notch1 and downstream effectors including Hes1, GATA3, RUNX3 and nuclear factor-kappa B (NF-kappa B) (p65 and p50), coincided with downregulation of the major transactivator Sp1 and its dissociation from Notch1 promoter. Overexpression of the Notch1 intracellular domain (NICD) significantly ameliorated bortezomib-induced cytotoxicity against T-ALL cells. Drug combination studies revealed that bortezomib showed synergistic or additive effects with key drugs for the treatment of T-ALL such as dexamethasone (DEX), doxorubicin and cyclophosphamide, which were readily abolished by NICD overexpression. The synergy of bortezomib and DEX was confirmed in vivo using a murine xenograft model. Our findings provide a molecular basis and rationale for the inclusion of proteasome inhibitors in treatment strategies for T-ALL.
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