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

Bots, M and Verbrugge, I and Martin, BP and Salmon, JM and Ghisi, M and Baker, A and Stanley, K and Shortt, J and Ossenkoppele, GJ and Zuber, J and Rappaport, AR and Atadja, P and Lowe, SW and Johnstone, RW (2014) Differentiation therapy for the treatment of t(8;21) acute myeloid leukemia using histone deacetylase inhibitors. Blood. pp. 1341-1352.

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. 2014 by The American Society of Hematology

Item Type: Article
Additional Information: NIBR author: Atadja, P institute: NIBR contributor address: (Bots, Verbrugge, Martin, Salmon, Ghisi, Baker, Stanley, Shortt, Johnstone) Cancer Therapeutics Program, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, VIC 3002, Australia (Ossenkoppele) Department of Hematology, Vrije Universiteit Medical Center, Amsterdam, Netherlands (Zuber, Rappaport, Lowe) Memorial Sloan Kettering Cancer Centre, New York, NY, United States (Atadja) China Novartis Institutes for Biomedical Health, Shanghai, China (Johnstone) Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia (Verbrugge) Division of Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands (Zuber) Research Institute of Molecular Pathology, Dr Bohr-Gasse 7, A-1030 Vienna, Austria
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22584

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