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 OwoeyeLewis R. Silverman, Steven D. Gore, Hetty E. Carraway

Research output: Contribution to journalArticle

Abstract

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 γ-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.

Original languageEnglish (US)
Pages (from-to)2764-2773
Number of pages10
JournalBlood
Volume114
Issue number13
DOIs
StatePublished - 2009

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

  • Cite this

    Fandy, T. E., Herman, J. G., Kerns, P., Jiemjit, A., Sugar, E. A., Choi, S. H., Yang, A. S., Aucott, T., Dauses, T., Odchimar-Reissig, R., Licht, J., McConnell, M. J., Nasrallah, C., Kim, M. K. H., Zhang, W., Sun, Y., Murgo, A., Espinoza-Delgado, I., Oteiza, K., ... Carraway, H. E. (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. Blood, 114(13), 2764-2773. https://doi.org/10.1182/blood-2009-02-203547