4.7 Article

Proteasome inhibitors exert cytotoxicity and increase chemosensitivity via transcriptional repression of Notch1 in T-cell acute lymphoblastic leukemia

期刊

LEUKEMIA
卷 28, 期 6, 页码 1216-1226

出版社

NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2013.366

关键词

T-cell acute lymphoblastic leukemia; Notch1; proteasome inhibitor; Sp1; chemosensitization

资金

  1. High-Tech Research Center Project for Private Universities: Matching Fund Subsidy from MEXT
  2. JSPS
  3. Japan Leukemia Research Fund
  4. Takeda Science Foundation
  5. Naito Foundation
  6. Yasuda Medical Foundation
  7. Mitsui Life Social Welfare Foundation
  8. Uehara Memorial Foundation
  9. Grants-in-Aid for Scientific Research [23591405, 26461430, 23591549, 25461434, 25118721] Funding Source: KAKEN

向作者/读者索取更多资源

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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