SP-7: The role of replication stress in the development of chromosomal alterations in myelodysplastic syndrome

Johanna Flach, Mannheim/Heidelberg

Summary

Hematopoietic stem cells (HSC) are responsible for the life-long production and replenishment of the blood, thereby making them one of the few blood cells that truly age. However, 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 myeolodysplastic syndrome (MDS). We have previously discovered that replication stress 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 and breaks. We further revealed that the replication stress features in old HSCs are caused by diminished expression of mini-chromosome maintenance (MCM) components. While it can be inferred from our study that replication stress may promote the acquisition of genomic aberrations, whether and 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 whether and how replication stress affects mitotic processes by inducing replication stress in young HSCs (in collaboration with Holger Bastians, SP2). We will take advantage of the central Z project to investigate the consequences of replication stress on specific genomic lesions in HSCs. In addition, we will examine the effects of diminished MCM expression on premitotic and mitotic abnormalities in HSCs. In collaboration with Zuzana Storchova (SP8) we will then investigate the molecular mechanisms that may be responsible for the aging-associated down-regulation of MCM components in HSCs. Ultimately, we will use HSCs isolated from MDS patients with and without aneuploidy and investigate features of replication stress in these cells with the overall goal to identify potential novel targets that can be exploited for future prognostic or therapeutic use.

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