Priority Programme 1463: "Epigenetic Regulation of Normal Hematopoiesis and its Dysregulation in Myeloid Neoplasia"
Epigenetic research, i.e. the evaluation of heritable gene expression patterns without changes in the DNA sequence, has primarily focussed on the regulation of highly coordinated developmental changes of cells and organisms, as well as disturbances of epigenetic mechanisms in hereditary and acquired human diseases, including cancer. Significant interest arises in the therapeutic potential of epigenetic mechanisms. In contrast to cancer-specific genetic alterations (mutations), cancer "epimutations" (i.e. functional gene inactivation) are pharmacologically reversible. The myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), constituting a biological continuum, have emerged as model diseases to study tumour (epi-)genomes and epigenetic therapy. AML is a rare tumour with a dismal prognosis in the majority of patients inflicted, and thus poses a highly unmet clinical need.
Currently, three research areas merge in cancer epigenetics, hematopoiesis, and myeloid malignancies:
- The advances in "deep sequencing" technology now permits genome-wide analyses of multiple epigenetic events on an unprecedented scale.
- A wealth of information on enzymatic epigenetic mechanisms has arisen in recent years. What lies ahead is to identify and manipulate specific epigenetic mechanisms that are at work in cancer cells and to explore applicability for diagnostic, therapeutic and prognostic approaches.
- Epigenetic drugs are in the process of approval for therapy of myeloid malignancies. The clinical experience with these drugs as well as the possibility to analyse the clinical specimens, with regard to changes in epigenetic markers, will be crucial for the understanding and utilisation of epigenetic strategies in myeloid malignancies.
The goal of the newly established Priority Programme is to enhance and to accelerate these merging fields and to shape the future of epigenetic research and therapy in the myeloid system. Six highly relevant research aims for this Programme have been identified:
- to define the epigenome of normal and myeloid leukemic hematopoietic cells by (epi-)genomewide, global profiling techniques
- to dissect the epigenetic regulation of hematopoietic stem cells and myeloid differentiation
- to investigate the role of key myeloid transcription factors (including C/EBP, PU.1, RUNX1) and of myeloid leukemia-specific fusion genes (including MLL fusions, PML/RARA, AML1/ETO, DEK/CAN) as epigenetic modifiers
- to search for novel epigenetic lesions in primary myeloid leukemia and preleukemia
- to develop preclinical models of epigenetic therapy of myeloid neoplasias
- to study the in vivo changes mediated by epigenetic therapy of myeloid neoplasias (i.e. hypomethylating agents, HDAC inhibitors)
To endow the Priority Programme with a strong focus, applications should fall within the following areas of research:
Epigenetic research, defined as the study of:
- DNA methylation
- posttranslational modifications of histones and myeloid-specific transcription factors
- enzymatic mechanisms of normal and transformed myeloid epigenesis
- RNA methylation (insofar as it relates to gene expression)
These mechanisms will be investigated in models of normal myeloid differentiation and of myeloid leukemia and preleukemia:
- normal granulocytes, monocytes, erythroid cells and platelets
- their neoplastic counterparts, i.e. acute myeloid leukemias, myelodysplastic and myeloproliferative syndromes, represented by cell line models and primary transformed human cells
- animal models of myeloid leukemias and preleukemias
The following research questions should be excluded:
- lymphoid malignancies and normal lymphoid development
- solid tumours (animal models, cell lines and primary tumours)
The following research questions should also be excluded, unless directly linked to epigenetic mechanisms:
- myeloid gene regulation on the transcriptional level
- myeloid-specific oncofusion proteins not directly linked to epigenetic alterations (e.g. BCR/ABL)
- murine models of myeloid leukemia not representative of epigenetic disturbances
- DNA damage and repair as mechanisms leading to chromosomal instability or chromosomal rearrangements (unless studied in the context of epigenetic therapy of myeloid neoplasia)
- nuclear structures and chromatin topology
- nuclear reprogramming or cell fusion
- cell cycle regulation or apoptosis without a direct link to epigenetic mechanisms
- drug development targeting non-epigenetic modifications in myeloid leukemia (e.g. activated tyrosine kinases and other frequently disturbed signalling pathways)
Proposals for an initial three-year funding period should be submitted on paper in triplicate (including appendices) and on CD-ROM. The CD-ROM should include the proposal and all appendices as PDF files. Proposals must be written in English, the title and the project summary should also be provided in German.
Please submit proposals, marked with the keyword "SPP 1463: Epigenetic Regulation" and addressed to the attention of Dr. Eckard Picht to the Deutsche Forschungsgemeinschaft, Kennedyallee 40, 53175 Bonn, by 2 November 2009. The review will be held during a proposal colloquium scheduled to take place in Bonn in March or April 2010.
For further details on the application process, please refer to DFG Guidelines 1.06, 1.06e and 1.02, 1.02e, available on the DFG homepage: www.dfg.de/forschungsfoerderung/formulare/schwerpunktprogramme.html