Johanna Ungerstedt group
We study global histone modifications and DNA methylation patterns in myelodysplastic syndromes (MDS). Our studies reach from bench to bedside, in vivo following treatment effects of epigenetically active drugs, and ex vivo culture of primary CD34+ early hematopoietic progenitor cells from patients and healthy subjects, for mechanistic studies.
The drugs of interest are azacytidine that is in clinical use, and histone deacetylase inhibitor (HDACi) Panobinostat, in clinical trials phase I /II trials for hematological malignancies. Azacytidine is a DNA demethylator, however its mechanism of action in vivo remains unclear.
In 2012 we will participate in a phase II combination trial with the two drugs. There is a great need for mechanistic studies of these drugs alone or in combination, and mapping of global histone effects, to understand the pathophysiology of disease and to help in identifying epigenetic profiles of MDS patient subpopulations that may benefit from treatment with these drugs.
We also study oxidative stress markers in MDS and normal bone marrow, and the effect of HDACi and azacytidine on intracellular redox systems.
Keywords: MDS, epigenetics, HDAC inhibitor, oxidative stress, azacytidine
Johanna Ungerstedt, Group Leader, MD, PhD.
She works as a resident doctor in Hematology, in combination with a research position at HERM, Department of Medicine, Huddinge.
|Hani Abdulkadi, PhD student|
|Deepika Nair, Masters student|
|Magnus Tobiasson, MD, specialist in Hematology, PhD student|
|Karolin Anderson, Student|
|Sergio Montano, PhD student|
1. Exploring the role of epigenetic alterations in high-risk myelodysplastic syndromes
Our aim is to map global epigenetic patterns (DNA methylation and histone modifications) in primary patient MDS cells cultured with and without azacytidine, to understand which modifications are mutually exclusive and which cluster together, and how they are associated with transcription levels.
This will increase our understanding of pathobiology of MDS disease, and the mechanism of action of azacytidine.
Another aim is to establish method for following epigenetic treatment effects and possible surrogate markers e.g. oxidative stress in peripheral blood monocytes.
This will have enormous practical impact as we cannot take bone marrow samples often, but if we can use peripheral blood we can monitor epigenetic changes over time in vivo. This knowledge will be used for studying patients treated with 5-azacytidine and or HDACi over time in an upcoming clinical trial.
2. Redox regulation in normal and malignant bone marrow
Studies of the distribution and regulation of redox protein systems in normal and MDS subtype RARS bone marrow, and the implications of knock down of redox proteins for erythroid cell maturation.
In this project we also study the redox effects elicited by HDACi and azacytidine.