Project Details
Projekt
Epigenetic Remodeling and Clonal Selection in a Murine Model of Accelerated Hematopoietic Stem Cell Aging.
Applicants
Privatdozent Dr. Daniel Lipka; Dr. Michael Milsom
Subject Area
Hematology, Oncology
Term
from 2017 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 336840530
During the process of aging, there is a progressive attrition of the hematopoietic stem cell (HSC) compartment, leading to the development of age-associated pathologies such as anemia, or the evolution of clonal hematopoiesis, which can then progress to MDS and leukemia. The gradual evolution of normal HSCs to their leukemic counterpart, via a pre-leukemic state, is a process that normally takes several decades in humans and is dependent on the coordinate acquisition of oncogenic mutations and epigenetic reprogramming. It would be highly desirable to gain further insight into this process from the perspective of risk assessment as well as both preventative and curative therapy for diseases such as MDS and AML. However, the extremely long time course of the development of disease makes mechanistic studies very challenging, as it is almost impossible to capture the instance where causative events occur. Surrogate models of this process must therefore be used. Unfortunately, the commonly used murine model of hematopoiesis fails to recapitulate several clinical features of aging. We postulate that the HSCs within normal laboratory mice are artificially protected from age-associated phenotypes by maintaining a long-term quiescent, or so-called dormant, state. HSC dormancy results from a lack of exposure to environmental stress stimuli, such as infection or inflammation, which are known to enforce HSC division in vivo. Unpublished data from our group demonstrate that chronic exposure of laboratory mice to such stress stimuli restores features of aged hematopoiesis in humans, and propose that this links to the well established clinical correlation between incidence of MDS/AML and history of chronic infection and inflammation. In this project, we will combine our expertise in low input epigenomic and genomic analysis with mouse models of HSC biology and stress hematopoiesis to characterize the functional erosion of these cells in response to stress and aging, while defining the underlying molecular process via which the HSC epigenome evolves during this process. Together with other Forschergruppe partners, we will then determine which genetic and epigenetic features of normal and malignant aged human hematopoiesis are likely driven by environmental stress.
DFG Programme
Research Units
