Project Details
Projekt
The role of chaperone-mediated autophagy in pre-leukemic hematopoietic stem cells
Applicant
Dr. Juliane Grimm
Subject Area
Hematology, Oncology
Term
from 2022 to 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 499544544
Hematopoietic stem cells (HSC) harbor extensive self-renewal capacities together with the ability to reside quiescent in their bone marrow niche which are the prerequisites for the life-long formation of mature blood cells. During aging, recurrent genetic alterations - especially in genes encoding epigentic modifiers - are frequently acquired in the HSC compartment. These mutations bestow HSC with increased multilineage repopulation capacity leading to their clonal expansion. Since these HSC are still able to give rise to the full range of healthy blood cells, the concept of pre-leukemic HSC was established. Large sequencing studies revealed that these pre-leukemic mutations could be identified in peripheral blood of otherwise healthy elderly individuals which resulted in the idea of age-related clonal hematopoiesis (ARCH). Thereby, the presence of ARCH was associated with an increased risk to develop acute myeloid leukemia (AML), as well as coronary heart disease and arteriosclerosis. Taken together these results suggest that the pool of aging pre-leukemic HSC most likely constitutes the origin of leukemia. However as only a small percentage of individuals with ARCH progress to AML the molecular mechanisms have not been fully understood.Recently, a study revealed the importance of chaperone-mediated autophagy (CMA) for the maintenance of HSC, especially during aging. Autophagy is essential for the decay of dysfunctional proteins and damaged cellular components, but also provides new resources (e.g. amino acids) when the cell is exposed to stress. Thereby, CMA is a selective subtype of autophagy as it specifically leads to lysosomal degradation of proteins with a target peptide motif. In HSC CMA is decreasing with age, and blocking CMA leads to a premature aged phenotype with high levels of reactive oxygen species and impaired glycolysis and fatty acid metabolism. These findings suggest that CMA is essential for HSC homeostasis, however the contribution of altered CMA to leukemogenesis has not been evaluated up to date.In the proposed research project, we will investigate how the impairment of CMA is involved in the phenotype of pre-leukemic HSC and their leukemic transformation potential using novel murine models of ARCH and primary human samples. The results of this study will provide a detailed cartography of CMA-dependent regulation of pre-leukemic ARCH HSC and ARCH leukemic stem cells. If successful, it might also help to establish strategies to interfere at a pre-leukemic level to prevent the rise of myeloid malignancies in the subgroup of individuals with particularly high risk of progression.
DFG Programme
WBP Fellowship
International Connection
USA
