Eradicating acute myeloid leukemia in a MllPTD/wt:Flt3ITD/wt murine model: a path to novel therapeutic approaches for human disease
| Autor: | Robert J. Lee, John S. Nemer, Ramasamy Santhanam, Daniel L. Brook, Jianying Zhang, Mengzi Zhang, G. Marcucci, Xiaoli Zhang, Susan P. Whitman, Michael A. Caligiuri, Guido Marcucci, Xiaojuan Yang, Kathryn E. Dickerson, Kathleen McConnell, William Blum, Adrienne M. Dorrance, Elshafa H. Ahmed, Kelsie M. Bernot, Shujun Liu, Ronald F. Siebenaler, Bethany L. Mundy-Bosse, Nicholas Zorko, Sabrina L Garman, Maura R. Muñoz |
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| Rok vydání: | 2013 |
| Předmět: |
FLT3 Internal Tandem Duplication
Myeloid Immunology MLL Partial Tandem Duplication Antineoplastic Agents Biology Biochemistry Bortezomib Mice immune system diseases hemic and lymphatic diseases medicine Animals Humans RNA Neoplasm neoplasms Drug Carriers Leukemia Experimental Myeloid Neoplasia Myeloid leukemia Histone-Lysine N-Methyltransferase Cell Biology Hematology DNA Methylation medicine.disease Boronic Acids Mice Mutant Strains Leukemia Myeloid Acute MicroRNAs Leukemia medicine.anatomical_structure fms-Like Tyrosine Kinase 3 Tandem Repeat Sequences Pyrazines Liposomes Mutation Fms-Like Tyrosine Kinase 3 Cancer research Myeloid-Lymphoid Leukemia Protein Proteasome Inhibitors medicine.drug |
| Zdroj: | Blood. 122:3778-3783 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2013-06-507426 |
| Popis: | 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: | OpenAIRE |
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