Entinostat Prevents Leukemia Maintenance in a Collaborating Oncogene-Dependent Model of Cytogenetically Normal Acute Myeloid Leukemia§

Authors


  • Author contributions: J.R. L.K., D.S., N.M., G. D., and P.A.: collection and/or assembly of data; J.B.: collection and/or assembly of data and final approval of manuscript, N.M.: provision of study material or patients; S.C.: data analysis and interpretation; T.L.: financial support and final approval of manuscript; S.Z.: data analysis and interpretation, K.I.M.: data analysis and interpretation and final approval of manuscript; J.K.: provision of study material or patients and manuscript writing; G.S.: conception and design and manuscript writing; A.T.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    first published online in STEM CELLS EXPRESS April 17, 2013.

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. STEM Cells2013;31:1434–1445

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