Entinostat prevents leukemia maintenance in a collaborating oncogene-dependent model of cytogenetically normal acute myeloid leukemia.

Abstract

The incidence of refractory acute myeloid leukemia (AML) is on the increase due in part to an aging population that fails to respond to traditional therapies. High throughput genomic analysis promises better diagnosis, prognosis, and therapeutic intervention based on improved patient stratification. Relevant preclinical models are urgently required to advance drug development in this area. The collaborating oncogenes, HOXA9 and MEIS1, are frequently co-overexpressed in cytogenetically normal AML (CN-AML), and a conditional transplantation mouse model was developed that demonstrated oncogene dependency and expression levels comparable to CN-AML patients. Integration of gene signatures obtained from the mouse model and a cohort of CN-AML patients using statistically significant connectivity map analysis identified Entinostat as a drug with the potential to alter the leukemic condition toward the normal state. Ex vivo treatment of leukemic cells, but not age-matched normal bone marrow controls, with Entinostat validated the gene signature and resulted in reduced viability in liquid culture, impaired colony formation, and loss of the leukemia initiating cell. Furthermore, in vivo treatment with Entinostat resulted in prolonged survival of leukemic mice. This study demonstrates that the HDAC inhibitor Entinostat inhibits disease maintenance and prolongs survival in a clinically relevant murine model of cytogenetically normal AML.

• Authors: Joanne M Ramsey, Laura M J Kettyle, Daniel J Sharpe, Nuala M Mulgrew, Glenda J Dickson, Janet J Bijl, Pamela Austin, Nadine Mayotte, Sonia Cellot, Terence R J Lappin, Shu-Dong Zhang, Ken I Mills, Jana Krosl, Guy Sauvageau, Alexander Thompson
• Journal: Stem cells (Dayton, Ohio) (Stem Cells) Vol. 31 Issue 7 Pg. 1434-45 (Jul 2013) ISSN: 1549-4918 [Electronic] England
• PMID: 23592435 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 AlphaMed Press.

Chemical References

• Benzamides
• Histone Deacetylase Inhibitors
• Pyridines
• entinostat

Topics

• Animals
• Benzamides (pharmacology)
• Gene Expression Profiling
• Gene Expression Regulation, Leukemic
• Histone Deacetylase Inhibitors (pharmacology)
• Immunophenotyping
• Leukemia, Myeloid, Acute (drug therapy, genetics, pathology)
• Mice
• Mice, Inbred C57BL
• Pyridines (pharmacology)