Please cite this article in press as: Karlic H, et al. The role of epigenetics in the regulation of apoptosis in myelodysplastic syndromes and
acute myeloid leukemia. Crit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2013.10.003
ARTICLE IN PRESS
ONCH-1801; No. of Pages 16
Critical Reviews in Oncology/Hematology xxx (2013) xxx–xxx
The role of epigenetics in the regulation of apoptosis in myelodysplastic
syndromes and acute myeloid leukemia
Heidrun Karlic
a,b,∗
, Harald Herrmann
a
, Franz Varga
c
, Roman Thaler
c
, Rene Reitermaier
a,b
,
Silvia Spitzer
c
, Viviane Ghanim
d
, Katharina Blatt
a,d
, Wolfgang R. Sperr
a,d
,
Peter Valent
a,d
, Michael Pfeilstöcker
a,b,e
a
Ludwig Boltzmann Cluster Oncology, Vienna, Austria
b
Ludwig Boltzmann Institute for Leukemia Research and Hematology, Hanusch Hospital, Vienna, Austria
c
Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling and 1st Medical Department,
Hanusch Hospital, Vienna, Austria
d
Department of Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria
e
3rd Medical Department, Hanusch Hospital, Vienna, Austria
Accepted 2 October 2013
Contents
1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.1. Epigenetic regulation of apoptosis in low risk MDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.2. Anti-apoptotic pathways in high risk MDS and AML . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.3. Key targets for epigenetic regulation of apoptosis in MDS and AML . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.4. Role of DNMT-targeting therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Epigenetic regulation of apoptosis and autophagy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1. Regulation of FAS and DAPK1 as well as tumor suppressor genes is associated with promoter methylation . . . . . . . . . . . . . . . 00
2.2. Expression of FAS on CD34
+
/CD38 and CD34
+
/CD38
+
stem and progenitor cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3. Drugs induce apoptosis as well as demethylation of FAS and DAPK1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.4. Do FAS- and/or DAPK signaling influence autophagy? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.5. siRNA-induced inhibition of FAS causes resistance against AZA and DAC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Author contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Abstract
Disordered stem cell epigenetics and apoptosis-regulating mechanisms contribute essentially to the pathogenesis of myelodysplastic
syndromes (MDS) and may trigger disease-progression to secondary acute myeloid leukemia (AML).
This study was supported by Fonds zur Förderung der Wissenschaftlichen Forschung in Österreich (FWF) grants #P21173-B13, SFB #04611, and the
Jubiläumsfonds der Österreichischen Nationalbank (#13068), Fund of the Mayor of the City of Vienna (Medizinisch-Wissenschaftlicher Fonds des Bürger-
meisters der Bundeshauptstadt Wien). The sponsors of this study are public or nonprofit organizations that support science in general. They had no role in
gathering, analyzing, or interpreting the data.
∗
Corresponding author at: Ludwig Boltzmann Cluster Oncology (LBI for Leukemia Research), Hanusch Hospital, Heinrich Collinstraße 30, A-1140 Vienna,
Austria. Tel.: +43 1 91021 86907; fax: +43 1 9143214.
E-mail addresses: heidrun.karlic@meduniwien.ac.at, heidrun.karlic@onc.lbg.ac.at (H. Karlic).
1040-8428/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.critrevonc.2013.10.003