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Blood, 24 September 2009, Vol. 114, No. 13, pp. 2764-2773. Prepublished online as a Blood First Edition Paper on June 22, 2009; DOI 10.1182/blood-2009-02-203547. This Article Full Text Full Text (PDF) Supplemental Tables and Figure All Versions of this Article: blood-2009-02-203547v1 114/13/2764    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Fandy, T. E. Articles by Carraway, H. E. PubMed PubMed Citation Articles by Fandy, T. E. Articles by Carraway, H. E. Related Collections Myeloid Neoplasia Clinical Trials and Observations Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies Tamer E. Fandy1, James G. Herman1, Patrick Kerns1, Anchalee Jiemjit1, Elizabeth A. Sugar2, Si-Ho Choi3, Allen S. Yang3, Timothy Aucott1, Tianna Dauses1, Rosalie Odchimar-Reissig4, Jonathan Licht5, Melanie J. McConnell6, Chris Nasrallah7, Marianne K. H. Kim5, Weijia Zhang8, Yezou Sun9, Anthony Murgo10, Igor Espinoza-Delgado10, Katharine Oteiza1, Ibitayo Owoeye1, Lewis R. Silverman4, Steven D. Gore1, and Hetty E. Carraway1 1 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD; 2 Departments of Epidemiology and Biostatistics, The Bloomberg School of Public Health at Johns Hopkins University, Baltimore, MD; 3 Division of Hematology, University of Southern California, Norris Cancer Center, Los Angeles; 4 Division of Medical Oncology, Mount Sinai Medical Center, New York, NY; 5 Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL; 6 Malaghan Institute of Medical Research, Wellington, New Zealand; 7 Center for Theoretical Evolutionary Genetics, University of California, Berkeley; 8 Division of Hematology/Oncology, Mount Sinai School of Medicine, New York, NY; 9 Personalized Medicine Research Program, Mount Sinai School of Medicine, New York, NY; and 10 Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD Sequential administration of DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors has demonstrated clinical efficacy in patients with hematologic malignancies. However, the mechanism behind their clinical efficacy remains controversial. In this study, the methylation dynamics of 4 TSGs (p15INK4B, CDH-1, DAPK-1, and SOCS-1) were studied in sequential bone marrow samples from 30 patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who completed a minimum of 4 cycles of therapy with 5-azacytidine and entinostat. Reversal of promoter methylation after therapy was observed in both clinical responders and nonresponders across all genes. There was no association between clinical response and either baseline methylation or methylation reversal in the bone marrow or purified CD34+ population, nor was there an association with change in gene expression. Transient global hypomethylation was observed in samples after treatment but was not associated with clinical response. Induction of histone H3/H4 acetylation and the DNA damage–associated variant histone -H2AX was observed in peripheral blood samples across all dose cohorts. In conclusion, methylation reversal of candidate TSGs during cycle 1 of therapy was not predictive of clinical response to combination "epigenetic" therapy. This trial is registered with http://www.clinicaltrials.gov under NCT00101179 [ClinicalTrials.gov] . CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Missteps in "tango" for epigenome targeting Keith D. Robertson and Kapil N. Bhalla Blood 2009 114: 2569-2570. [Full Text] [PDF] This article has been cited by other articles: M. E. Figueroa, L. Skrabanek, Y. Li, A. Jiemjit, T. E. Fandy, E. Paietta, H. Fernandez, M. S. Tallman, J. M. Greally, H. Carraway, et al. MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation Blood, October 15, 2009; 114(16): 3448 - 3458. [Abstract] [Full Text] [PDF] K. D. Robertson and K. N. Bhalla Missteps in "tango" for epigenome targeting Blood, September 24, 2009; 114(13): 2569 - 2570. [Full Text] [PDF]

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