| Autor: |
Bernot KM; The Ohio State University Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH;, Nemer JS, Santhanam R, Liu S, Zorko NA, Whitman SP, Dickerson KE, Zhang M, Yang X, McConnell KK, Ahmed EH, Muñoz MR, Siebenaler RF, Marcucci GG, Mundy-Bosse BL, Brook DL, Garman S, Dorrance AM, Zhang X, Zhang J, Lee RJ, Blum W, Caligiuri MA, Marcucci G |
| Jazyk: |
angličtina |
| Zdroj: |
Blood [Blood] 2013 Nov 28; Vol. 122 (23), pp. 3778-83. Date of Electronic Publication: 2013 Oct 01. |
| DOI: |
10.1182/blood-2013-06-507426 |
| Abstrakt: |
The coexpression of the MLL partial tandem duplication (PTD) and the FLT3 internal tandem duplication (ITD) mutations associate with a poor outcome in cytogenetically normal acute myeloid leukemia (AML). In mice, a double knock-in (dKI) of Mll(PTD/wt) and Flt3(ITD/wt) mutations induces spontaneous AML with an increase in DNA methyltransferases (Dnmt1, 3a, and 3b) and global DNA methylation index, thereby recapitulating its human AML counterpart. We determined that a regulator of Dnmts, miR-29b, is downregulated in bone marrow of dKI AML mice. Bortezomib exerted a dose-dependent increase in miR-29b expression in AML blasts ex vivo, followed by decreased Dnmts, reduced proliferation, and increased apoptosis. In vivo, bortezomib was not active against dKI AML, yet liposomal-encapsulated bortezomib, as a single agent, reversed downregulation of miR-29b in vivo and induced a long-term (90-day) disease-free remission in 80% of dKI AML mice that exhibited high leukemic burden at the start of therapy, yet showed no signs of relapse at autopsy. Taken together, these data support that liposomal bortezomib, as a single agent, eradicates Mll(PTD/wt):Flt3(ITD/wt) AML in mouse and may represent a powerful and potentially curative approach to high-risk human disease. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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