PMID- 30470836
OWN - NLM
STAT- MEDLINE
DCOM- 20190809
LR  - 20220420
IS  - 1476-5551 (Electronic)
IS  - 0887-6924 (Linking)
VI  - 33
IP  - 4
DP  - 2019 Apr
TI  - Combination treatment of acute myeloid leukemia cells with DNMT and HDAC 
      inhibitors: predominant synergistic gene downregulation associated with gene body 
      demethylation.
PG  - 945-956
LID - 10.1038/s41375-018-0293-8 [doi]
AB  - DNA methyltransferase inhibitors (DNMTi) approved for older AML patients are 
      clinically tested in combination with histone deacetylase inhibitors (HDACi). The 
      mechanism of action of these drugs is still under debate. In colon cancer cells, 
      5-aza-2'-deoxycytidine (DAC) can downregulate oncogenes and metabolic genes by 
      reversing gene body DNA methylation, thus implicating gene body methylation as a 
      novel drug target. We asked whether DAC-induced gene body demethylation in AML 
      cells is also associated with gene repression, and whether the latter is enhanced 
      by HDACi.Transcriptome analyses revealed that a combined treatment with DAC and 
      the HDACi panobinostat or valproic acid affected significantly more transcripts 
      than the sum of the genes regulated by either treatment alone, demonstrating a 
      quantitative synergistic effect on genome-wide expression in U937 cells. This 
      effect was particularly striking for downregulated genes. Integrative methylome 
      and transcriptome analyses showed that a massive downregulation of genes, 
      including oncogenes (e.g., MYC) and epigenetic modifiers (e.g., KDM2B, SUV39H1) 
      often overexpressed in cancer, was associated predominantly with gene body DNA 
      demethylation and changes in acH3K9/27. These findings have implications for the 
      mechanism of action of combined epigenetic treatments, and for a better 
      understanding of responses in trials where this approach is clinically tested.
FAU - Blagitko-Dorfs, Nadja
AU  - Blagitko-Dorfs N
AD  - Division of Hematology, Oncology and Stem Cell Transplantation, Department of 
      Internal Medicine, Faculty of Medicine and Medical Center, University of 
      Freiburg, Freiburg, Germany.
AD  - Center for Chronic Immunodeficiency (CCI), Medical Center - University of 
      Freiburg, Freiburg, Germany.
FAU - Schlosser, Pascal
AU  - Schlosser P
AUID- ORCID: 0000-0002-8460-0462
AD  - Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, 
      University of Freiburg, Freiburg, Germany.
FAU - Greve, Gabriele
AU  - Greve G
AD  - Division of Hematology, Oncology and Stem Cell Transplantation, Department of 
      Internal Medicine, Faculty of Medicine and Medical Center, University of 
      Freiburg, Freiburg, Germany.
FAU - Pfeifer, Dietmar
AU  - Pfeifer D
AD  - Division of Hematology, Oncology and Stem Cell Transplantation, Department of 
      Internal Medicine, Faculty of Medicine and Medical Center, University of 
      Freiburg, Freiburg, Germany.
FAU - Meier, Ruth
AU  - Meier R
AD  - Division of Hematology, Oncology and Stem Cell Transplantation, Department of 
      Internal Medicine, Faculty of Medicine and Medical Center, University of 
      Freiburg, Freiburg, Germany.
FAU - Baude, Annika
AU  - Baude A
AD  - Division of Epigenomics and Cancer Risk Factors, DKFZ, Heidelberg, Germany.
FAU - Brocks, David
AU  - Brocks D
AD  - Division of Epigenomics and Cancer Risk Factors, DKFZ, Heidelberg, Germany.
FAU - Plass, Christoph
AU  - Plass C
AUID- ORCID: 0000-0003-2554-3952
AD  - Division of Epigenomics and Cancer Risk Factors, DKFZ, Heidelberg, Germany.
FAU - Lubbert, Michael
AU  - Lubbert M
AD  - Division of Hematology, Oncology and Stem Cell Transplantation, Department of 
      Internal Medicine, Faculty of Medicine and Medical Center, University of 
      Freiburg, Freiburg, Germany. michael.luebbert@uniklinik-freiburg.de.
AD  - DKTK, German Consortium for Translational Cancer Research, Freiburg, Germany. 
      michael.luebbert@uniklinik-freiburg.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181123
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 614OI1Z5WI (Valproic Acid)
RN  - 776B62CQ27 (Decitabine)
RN  - 9647FM7Y3Z (Panobinostat)
RN  - EC 2.1.1.- (DNA Modification Methylases)
MH  - Biomarkers, Tumor/genetics
MH  - *DNA Methylation
MH  - DNA Modification Methylases/antagonists & inhibitors
MH  - Decitabine/*pharmacology
MH  - Demethylation
MH  - Down-Regulation
MH  - *Drug Synergism
MH  - Enzyme Inhibitors/*pharmacology
MH  - Epigenesis, Genetic
MH  - *Gene Expression Regulation, Neoplastic
MH  - Histone Deacetylase Inhibitors/*pharmacology
MH  - Humans
MH  - Leukemia, Myeloid, Acute/drug therapy/*genetics/pathology
MH  - Panobinostat/pharmacology
MH  - Valproic Acid/pharmacology
OTO - NOTNLM
OT  - TINAT
OT  - cancer-testis antigen (CTA)
EDAT- 2018/11/25 06:00
MHDA- 2019/08/10 06:00
CRDT- 2018/11/25 06:00
PHST- 2016/06/15 00:00 [received]
PHST- 2018/09/06 00:00 [accepted]
PHST- 2018/06/21 00:00 [revised]
PHST- 2018/11/25 06:00 [pubmed]
PHST- 2019/08/10 06:00 [medline]
PHST- 2018/11/25 06:00 [entrez]
AID - 10.1038/s41375-018-0293-8 [pii]
AID - 10.1038/s41375-018-0293-8 [doi]
PST - ppublish
SO  - Leukemia. 2019 Apr;33(4):945-956. doi: 10.1038/s41375-018-0293-8. Epub 2018 Nov 
      23.