Project Details
Projekt
The role of replication stress in the development of chromosomal alterations in myelodysplastic syndrome
Applicant
Dr. Johanna Flach
Subject Area
Cell Biology
Term
from 2018 to 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 395736209
Hematopoietic stem cells (HSCs) are responsible for the lifelong production and replenishment of the blood, thereby making them one of the few blood cell types that truly age. As in any aging tissue, their functional activity declines with increasing age as reflected in impaired engraftment following transplantation, a decline in immunocompetence and a higher predisposition for the development of myeloid malignancies, particularly myelodysplastic syndrome (MDS), which is characterized by numerical and structural chromosome aberrations. We have previously discovered that replication stress (RS) constitutes a major driver underlying the HSC functional decline with increasing age. This is associated with altered dynamics of DNA replication forks leading to cell cycle defects and chromosome gaps/breaks. We further revealed that the RS features in old HSCs are caused by diminished expression of mini-chromosome maintenance (MCM) components. While it can be inferred from our study that RS may promote the acquisition of genomic aberrations, how it may be driving the accumulation of clonal chromosomal abnormalities, particularly whole and segmental chromosome aneuploidy that is known to be critical in the pathogenesis of MDS, remains unknown. In the proposed project we will address how RS affects mitotic processes by inducing RS in young HSCs (in collaboration with Holger Bastians, SP2). In collaboration with the Z-project, SP-Z, we will further investigate the consequences of RS on specific genomic lesions in HSCs. In addition, we will examine the effects of diminished MCM expression on mitotic abnormalities. In collaboration with Zuzana Storchova, SP8, we will then investigate the molecular mechanisms that may be responsible for the aging-associated downregulation of MCM components in HSCs, in particular testing the impact of protein folding capacity on MCM levels and modifications. Ultimately, we will use HSCs isolated from MDS patients with and without aneuploidy and investigate features of RS in these cells with the overall goal to identify potential novel targets that can be exploited for future prognostic or therapeutic use.
DFG Programme
Research Units
