Bots, M., Verbrugge, I., Martin, B. P., Salmon, J. M., Ghisi, M., Baker, A., Stanley, K., Shortt, J., Ossenkoppele, G. J., Zuber, J., Rappaport, A. R., Atadja, P., Lowe, S. W., Johnstone, R. W. (February 2014) Differentiation therapy for the treatment of t(8;21) acute myeloid leukemia using histone deacetylase inhibitors. Blood, 123 (9). pp. 1341-52. ISSN 0006-4971
Abstract
Epigenetic modifying enzymes such as histone deacetylases (HDACs), p300, and PRMT1 are recruited by AML1/ETO, the pathogenic protein for t(8;21) acute myeloid leukemia (AML), providing a strong molecular rationale for targeting these enzymes to treat this disease. Although early phase clinical assessment indicated that treatment with HDAC inhibitors (HDACis) may be effective in t(8;21) AML patients, rigorous preclinical studies to identify the molecular and biological events that may determine therapeutic responses have not been performed. Using an AML mouse model driven by expression of AML1/ETO9a (A/E9a), we demonstrated that treatment of mice bearing t(8;21) AML with the HDACi panobinostat caused a robust antileukemic response that did not require functional p53 nor activation of conventional apoptotic pathways. Panobinostat triggered terminal myeloid differentiation via proteasomal degradation of A/E9a. Importantly, conditional A/E9a deletion phenocopied the effects of panobinostat and other HDACis, indicating that destabilization of A/E9a is critical for the antileukemic activity of these agents.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Animals Antineoplastic Agents/*therapeutic use Cell Differentiation/*drug effects/genetics/immunology Cells, Cultured Chromosomes, Human, Pair 21/genetics Chromosomes, Human, Pair 8/genetics Core Binding Factor Alpha 2 Subunit/genetics Disease Models, Animal Embryo, Mammalian Histone Deacetylase Inhibitors/*therapeutic use Humans Hydroxamic Acids/*therapeutic use Indoles/*therapeutic use Leukemia, Myeloid, Acute/*drug therapy Mice Mice, Inbred C57BL Mice, Transgenic Oncogene Proteins, Fusion/genetics Translocation, Genetic |
| Subjects: | diseases & disorders > cancer > drugs and therapies bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > histone deacetylase diseases & disorders > cancer > cancer types > leukemia |
| CSHL Authors: | |
| Communities: | CSHL labs > Lowe lab School of Biological Sciences > Publications |
| Depositing User: | Matt Covey |
| Date: | 27 February 2014 |
| Date Deposited: | 23 Sep 2014 14:02 |
| Last Modified: | 23 Sep 2014 14:03 |
| PMCID: | PMC3938147 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/30801 |
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