FOR 2674:  Aging-related epigenetic remodeling in acute myeloid leukemia

• Subject Area: Medicine
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 336840530

Older age is a major risk factor for cancer development. However, the distinct pathobiology of malignancies occurring with age is not understood. Acute myeloid leukemia (AML) represents a prototypical neoplasia of older individuals, with many clinical challenges: most patients are >65 years of age, have adverse genetic features, comorbidities, and their leukemia stem cells are very difficult to eradicate, resulting in a low cure rate even with aggressive chemotherapy. Investigations of the aberrant epigenome of AML cells, and the vision to therapeutically remodel it by pharmacological means, have resulted in three recent breakthrough developments which, in concert, are driving the present initiative. First, recurrent, frequent somatic mutations in genes encoding enzymes which shape the epigenome (DNMT3A, TET2, IDH1/2 etc.) have been discovered in AML, providing a genetic foundation for the view that aberrant epigenetic remodeling has a causative role in cancer. Second, these mutations have very recently been described in apparently normal hematopoietic cells of older individuals, driving their clonal expansion and probably representing a preleukemic event in hematopoietic stem and progenitor cells. Third, drugs which reduce the aberrant DNA methylation of AML (hypomethylating agents, HMAs) have recently become the first approved treatment for older AML patients. Despite these advances, relatively little is known about the interaction between genetic events occurring in older AML patients and the epigenome of the leukemia stem cells and their progeny, the interaction with epigenetic drugs, and the role of cell aging processes. In order to advance our knowledge at the intersection of these distinct areas of research, we propose the present initiative, which brings together experts in the fields of aging, stem cell research, epigenetics and AML. Combining the different expertises in this emerging field, we shall pursue the following goals:1. To unravel the genome-epigenome interactions in leukemic precursor cells (down to the single-cell level) in human AML and in mouse models, including profiling for different histone modifications. 2. To identify novel "driver" somatic mutations in AML of older patients using whole-genome sequencing approaches. 3. To provide insights in the "aging clock" of AML cells in patients with a very indolent disease course (so-called "smoldering AML").4. To better understand the "age factor" inherent in AML of the elderly which mediates the inferior clinical outcome even in the presence of good-risk genetic features.5. To elucidate the in vivo mechanisms of action of HMAs and other chromatin-modifying agents in elderly AML patients, in order to devise rational drug combinations including immunotherapeutic approaches. The ultimate aim of the present initiative is to improve the prognosis of elderly AML patients with the outlook to extend this knowledge to other, more frequent cancers of the elderly.

• DFG Programme: Research Units

Projects

• Alterations of H3K9me2 in hematopoietic stem cells: implications for aging and myeloid leukemogenesis (Applicant Geiger, Hartmut )
• Bioinformatics of epigenome data and integrative analysis (Applicants Brors, Benedikt ;  Mughal, Ph.D., Sadaf )
• Coordination Funds (Applicant Lübbert, Ph.D., Michael )
• Deciphering Critical Changes in the Methylome of Hematopoietic Stem Cells in Age-related Clonal Hematopoiesis and Myeloid Leukemogenesis (Applicants Buske, Christian ;  Plass, Christoph )
• Dissecting AML transcriptome and chromatin networks by single cell sequencing to reveal cell heterogeneity and drug response mechanisms (Applicants Mallm, Jan-Philipp ;  Rippe, Karsten )
• Dissecting molecular basis and cellular heterogeneity of slow progressing 'smoldering' AMLs of the elderly (Applicants Dierks, Christine ;  Trumpp, Ph.D., Andreas )
• Epigenetic Remodeling and Clonal Selection in a Murine Model of Accelerated Hematopoietic Stem Cell Aging. (Applicants Lipka, Daniel ;  Milsom, Michael )
• Genetic Landscape of Acute Myeloid Leukemia (AML) in Older Patients (Applicants Bullinger, Lars ;  Döhner, Hartmut ;  Döhner, Konstanze )
• Molecular mechanisms of epigenetic therapies (Applicants Goyal, Ph.D., Ashish ;  Lübbert, Ph.D., Michael ;  Plass, Christoph )
• Regulation of the histone 4 epigenetic landscape upon hematopoietic stem cell aging (Applicant Geiger, Hartmut )
• The DNA methylome as a therapeutic target in elderly patients with acute myeloid leukemia: Development of combination treatments (Applicants Becker, Heiko ;  Lübbert, Ph.D., Michael )
• The role of the histone demethylase LSD1 in the pathogenesis of AML (Applicants Pahl, Heike L. ;  Schüle, Roland )

• Spokesperson: Professor Michael Lübbert, Ph.D.