Differentiation therapy for the treatment of t(8;21) acute myeloid leukemia using histone deacetylase inhibitors

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

URL: http://www.ncbi.nlm.nih.gov/pubmed/24415537
DOI: 10.1182/blood-2013-03-488114

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
Watson School > 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: http://repository.cshl.edu/id/eprint/30801

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