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

التفاصيل البيبلوغرافية
العنوان: Entinostat Prevents Leukemia Maintenance in a Collaborating Oncogene-Dependent Model of Cytogenetically Normal Acute Myeloid Leukemia
المؤلفون: Joanne M. Ramsey, Nadine Mayotte, Terence R.J. Lappin, Jana Krosl, Janet J. Bijl, Guy Sauvageau, Nuala M. Mulgrew, Pamela Austin, Ken I. Mills, Shu-Dong Zhang, Alexander Thompson, Glenda J. Dickson, Sonia Cellot, Laura M. Kettyle, Daniel J. Sharpe
المصدر: Stem Cells. 31:1434-1445
بيانات النشر: Oxford University Press (OUP), 2013.
سنة النشر: 2013
مصطلحات موضوعية: Pyridines, medicine.drug_class, Biology, Immunophenotyping, Mice, chemistry.chemical_compound, medicine, Animals, Oncogene, Gene Expression Regulation, Leukemic, Entinostat, Gene Expression Profiling, Histone deacetylase inhibitor, Myeloid leukemia, Cell Biology, Gene signature, medicine.disease, Histone Deacetylase Inhibitors, Mice, Inbred C57BL, Transplantation, Leukemia, Myeloid, Acute, Leukemia, chemistry, Benzamides, Immunology, Cancer research, Molecular Medicine, Ex vivo, Developmental Biology
الوصف: 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.
تدمد: 1549-4918
1066-5099
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dea5683156f620af7ac8e772e4e176c8
https://doi.org/10.1002/stem.1398
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....dea5683156f620af7ac8e772e4e176c8
قاعدة البيانات: OpenAIRE