SPP 1463:  Epigenetic Regulation of Normal Hematopoiesis and its Dysregulation in Myeloid Neoplasia

• Subject Area: Medicine
• Term: from 2010 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 130238942

Cancer epigenomics is a research area that drives the development of novel and innovative methodologies to study genome-wide epigenetic patterns, drug discovery and development, and novel therapeutic approaches targeting the cancer-specific epigenetic defects. Here myeloid cancers such as acute myeloid leukemia (AML) and the preleukemic myelodysplastic syndromes (MDS) have emerged as model diseases to study the cancer (epi)genome.
The cancer epigenetics field, especially in hematopoiesis and myeloid malignancies, has reached a corner stone by the merge of three research areas. First, technological advances allow genome-wide identification and characterisation of epigenetic alterations in myeloid cells. Second, the recent increase in the understanding of epigenetic mechanisms in non-transformed cells leads to the challenge of identifying and determining the specific epigenetic mechanisms at work in cancer cells and their applicability for diagnostic, therapeutic and prognostic approaches. Third, the clinical experience with drugs now being in the process of approval for therapy as well as the possibility to analyse clinical specimens with regard to changes in epigenetic markers will be crucial to understand and utilise epigenetic strategies in myeloid malignancies. These three increasingly overlapping research areas lead to the emerging new field: epigenetic events and therapy in myelopoiesis and myeloid malignancy.
This Priority Programme is intended to contribute to a better understanding of epigenetic mechanisms regulating gene expression in normal hematopoiesis and myeloid neoplasia (focussing on acute myeloid leukemia and myelodysplastic syndromes), and to translate this understanding into novel and effective therapies. To achieve this goal, we have formulated the following five aims of the Priority Programme: (1) to define the epigenome of normal and myeloid leukemic hematopoietic cells by (epi)genome-wide, global profiling techniques; (2) to dissect epigenetic regulation of hematopoietic stem cell protection and myeloid differentiation; (3) to investigate the role of key myeloid transcription factors and of myeloid leukemia-specific fusion genes as epigenetic modifiers; (4) to search for novel genetic and epigenetic lesions in primary myeloid leukemia and preleukemia; (5) to develop preclinical models of epigenetic therapy of myeloid neoplasias.

• DFG Programme: Priority Programmes

Projects

• Combined epigenetic therapy of acute myeloid leukemia: translational studies of in vivo induction of gene expression and DNA hypomethylation (Applicant Lübbert, Ph.D., Michael )
• Comparative characterization of azacytidine-induced RNA and DNA demethylation in myeloid leukemia (Applicant Lyko, Frank )
• Computational model of epigenetic regulation of myeloid differentiation during homoeostasis and malignant transformation (Applicants Galle, Jörg ;  Löffler, Markus )
• Coordination Funds (Applicants Lübbert, Ph.D., Michael ;  Plass, Christoph )
• Development of integrative methods for the analysis of epigenetic data on myeloid neoplasia (Applicant Brors, Benedikt )
• Disordered epigenetic regulation of the CREBBP oncoprotein and of micro-RNA transcription in juvenile myelomonocytic leukemia at high risk of relapse (Applicant Flotho, Christian )
• Dissecting the role of PIWIL4 as a novel epigenetic factor in acute myeloid leukemia (Applicants Buske, Christian ;  Rawat, Ph.D., Vijay Pal Singh )
• Epigenetic consequences of MLL fusion protein expression (Applicant Slany, Robert )
• Epigenetic dysregulation of transcription factor NF-E2 expression in thepathophysiology of myeloproliferative neoplasms (Applicant Pahl, Heike L. )
• Epigenetic function of RUNX1 with PRMT6 in normal and aberrant myeloid differentiation (Applicant Lausen, Jörn )
• Epigenetics of the nuclear oncoprotein Ski in AML (Applicant Neubauer, Andreas )
• Functional analysis of aberrant DNA methylation in acute myeloid leukemia (Applicant Rehli, Michael )
• Functional analysis of KDM6A histone demethylase in the regulation of HSC development and in leukemogenesis (Applicants Becker, Matthias ;  Müller, Albrecht M. )
• Functional analysis of somatic cancer mutations in human DNA methyltransferases (Applicant Jeltsch, Albert )
• Functional evaluation of DNA methylation-controlled leukemia stem cell genes (Applicants Andrade-Navarro, Ph.D., Miguel ;  Rosenbauer, Frank )
• Functional examination of H3K4 methyltransferases in myeloid neoplasia (Applicants Kranz, Andrea ;  Stewart, Adrian Francis )
• Genetic and epigenetic search for tumor suppressor genes on chromosome 7q in acute myeloid leukemia (Applicants Döhner, Hartmut ;  Plass, Christoph )
• Reversible histone acetylation and its inhibitors in myeloid neoplasia (Applicant Jung, Manfred )
• The role of TET proteins in myeloid neoplasia (Applicants Bohlander, Stefan Klaus ;  Leonhardt, Heinrich ;  Spiekermann, Karsten )
• The significance of DNA Methyltransferase inhibition and DNA Methylation for therapy response in Acute Myeloid Leukemia (Applicant Müller-Tidow, Carsten )

• Spokespersons: Professor Michael Lübbert, Ph.D.; Professor Dr. Christoph Plass