Eradicating acute myeloid leukemia in a MllPTD/wt:Flt3ITD/wt murine model: a path to novel therapeutic approaches for human disease
Year: 2013
Type: article
Abstract: 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.
Source: Blood
Authors: Kelsie M. Bernot, John S. Nemer, Ramasamy Santhanam, Shujun Liu, Nicholas A. Zorko, Susan P. Whitman, Kathryn E. Dickerson, Mengzi Zhang, Xiaojuan Yang, Kathleen K. McConnell, Elshafa H. Ahmed, Maura R. Muñoz, Ronald F. Siebenaler, Gabriel G. Marcucci, Bethany L. Mundy-Bosse, Daniel L. Brook, Sabrina Garman, Adrienne M. Dorrance, Xiaoli Zhang, Jianying Zhang, Robert J. Lee, William Blum, Michael A. Caligiuri, Guido Marcucci
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2031202802