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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 (PDF) Supplemental Tables and Figure All Versions of this Article: blood-2009-02-203547v1 114/13/2764    most recent e-Letter: Submit a Response Alert me when this article is cited Alert me when e-Letters are posted Alert me if a correction is posted 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 Citing Articles via Google Scholar Google Scholar Articles by Fandy, T. E. Articles by Carraway, H. E. Search for Related Content PubMed PubMed Citation Articles by Fandy, T. E. Articles by Carraway, H. E. Related Collections Related Article in Blood Online Social Bookmarking                         What's this?  Previous Article  |  Next Article  Submitted February 24, 2009 Accepted May 14, 2009 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. Fandy, James G. Herman, Patrick Kerns, Anchalee Jiemjit, Elizabeth A. Sugar, Si-Ho Choi, Allen S. Yang, Timothy Aucott, Tianna Dauses, Rosalie Odchimar-Reissig, Jonathan Licht, Melanie J. McConnell, Chris Nasrallah, Marianne K.H. Kim, Weijia Zhang, Yezou Sun, Anthony Murgo, Igor Espinoza-Delgado, Katharine Oteiza, Ibitayo Owoeye, Lewis R. Silverman, Steven D. Gore*, and Hetty E. Carraway The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, United States Departments of Epidemiology and Biostatistics, The Bloomberg School of Public Health at Johns Hopkins, Baltimore, MD, United States Division of Hematology, University of Southern California, Norris Cancer Center, Los Angeles, CA, United States Division of Medical Oncology, Mount Sinai Medical Center, New York, NY, United States Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States Malaghan Institute of Medical Research, Wellington South, New Zealand Center for Theoretical Evolutionary Genetics, University of California, Berkeley, CA, United States Division of Hematology/Oncology, Mount Sinai School of Medicine, New York, NY, United States Personalized Medicine Research Program, Mount Sinai School of Medicine, New York, NY, United States Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD, United States * Corresponding author; email: gorest{at}jhmi.edu. Sequential administration of DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors has demonstrated clinical efficacy in patients with hematological malignancies. These combinations were designed to effect optimal re-expression of epigenetically silenced tumor suppressor genes (TSG); however, this hypothesis remains controversial. In this study, the methylation dynamics of four TSG (p15INK4B, CDH-1, DAPK-1 and SOCS-1) were studied in sequential bone marrow samples from 30 patients with MDS or AML who completed a minimum of 4 cycles of therapy with 5-azacytidine and entinostat. Reversal of promoter methylation following therapy was observed in both clinical responders and non-responders 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 following treatment but was not associated with clinical response. Induction of histone H3/H4 acetylation in peripheral blood samples was observed post therapy. Induction of the DNA damage-associated variant histone -H2AX was observed in peripheral blood samples across all dose cohorts. In conclusion, methylation reversal of candidate TSG during cycle one of therapy was not predictive of clinical response to combination 'epigenetic' therapy. This trial is registered with www.clinicaltrials.gov under NCT00101179. CiteULike    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    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: B. Salhia, A. Baker, G. Ahmann, D. Auclair, R. Fonseca, and J. Carpten DNA Methylation Analysis Determines the High Frequency of Genic Hypomethylation and Low Frequency of Hypermethylation Events in Plasma Cell Tumors Cancer Res., September 1, 2010; 70(17): 6934 - 6944. [Abstract] [Full Text] [PDF] J. D. Kagey, P. Kapoor-Vazirani, M. T. McCabe, D. R. Powell, and P. M. Vertino Long-term Stability of Demethylation after Transient Exposure to 5-Aza-2'-Deoxycytidine Correlates with Sustained RNA Polymerase II Occupancy Mol. Cancer Res., July 1, 2010; 8(7): 1048 - 1059. [Abstract] [Full Text] [PDF] E. Schafer, R. Irizarry, S. Negi, E. McIntyre, D. Small, M. E. Figueroa, A. Melnick, and P. Brown Promoter hypermethylation in MLL-r infant acute lymphoblastic leukemia: biology and therapeutic targeting Blood, June 10, 2010; 115(23): 4798 - 4809. [Abstract] [Full Text] [PDF] 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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