Potential Relationship between Inadequate Response to DNA Damage and Development of Myelodysplastic Syndrome

Abstract

Hematopoietic stem cells (HSCs) are responsible for the continuous regeneration of all types of blood cells, including themselves. To ensure the functional and genomic integrity of blood tissue, a network of regulatory pathways tightly controls the proliferative status of HSCs. Nevertheless, normal HSC aging is associated with a noticeable decline in regenerative potential and possible changes in other functions. Myelodysplastic syndrome (MDS) is an age-associated hematopoietic malignancy, characterized by abnormal blood cell maturation and a high propensity for leukemic transformation. It is furthermore thought to originate in a HSC and to be associated with the accrual of multiple genetic and epigenetic aberrations. This raises the question whether MDS is, in part, related to an inability to adequately cope with DNA damage. Here we discuss the various components of the cellular response to DNA damage. For each component, we evaluate related studies that may shed light on a potential relationship between MDS development and aberrant DNA damage response/repair.

Ssb1 and Ssb2 cooperate to regulate mouse hematopoietic stem and progenitor cells by resolving replicative stress

“…38,39 The longevity and proliferative capacity of myeloid progenitor cells renders them particularly susceptible to DNA damage. 40 Analysis of BM populations by flow cytometry revealed a dramatic reduction in committed myeloid progenitor cells (lineage Figure 2F). Once equivalent engraftment of donor cells of all genotypes was confirmed at 4 weeks, the recipient mice were treated with 1 mg of TAM once daily for 5 days.…”

Genetic Variant Screening of DNA Repair Genes in Myelodysplastic Syndrome Identifies a Novel Mutation in the <b><i>XRCC2</i></b> Gene

“…The number of various genetic and cytogenetic alterations described in the last few years [5-7, 9] and our recent results showing deregulated DNA repair gene expression in MDS cases [21] support the theory that MDS is a disease of genomic instability [10]. Though mutations in the TP53 gene and their relationship with MDS are already known, no mutations in genes directly involved in DNA repair have been described.…”

“…Considering the high incidence of mutations and cytogenetic alterations [9], it may be assumed that genomic instability plays a role in MDS pathogenesis. Genomic instability can be defined as the increased susceptibility of cells to acquire and spread genomic mutations or the inability of cells to deal with DNA damage [10]. There is growing evidence that the DNA damage response (DDR) or DNA repair machinery is impaired in MDS cells [11].…”

Genetic variants involved in oxidative stress, base excision repair, DNA methylation, and folate metabolism pathways influence myeloid neoplasias susceptibility and prognosis

“…AML is defined as a clonal disorder of hematopoietic progenitor cells with a severe arrest of myeloid differentiation that can arise from different chromosomal aberrations or gene mutations . However, MDS and AML share some common features, such as: oxidative stress , DNA repair deficiency , and aberrant DNA methylation .…”