Myelodysplastic syndrome: an inability to appropriately respond to damaged DNA?

Abstract

Myelodysplastic syndrome (MDS) is considered a hematopoietic stem cell disease that is characterized by abnormal hematopoietic differentiation and a high propensity to develop acute myeloid leukemia. It is mostly associated with advanced age, but also with prior cancer therapy and inherited syndromes related to abnormalities in DNA repair. Recent technologic advances have led to the identification of a myriad of frequently occurring genomic perturbations associated with MDS. These observations suggest that MDS and its progression to acute myeloid leukemia is a genomic instability disorder, resulting from a stepwise accumulation of genetic abnormalities. The notion is now emerging that the underlying mechanism of this disease could be a defect in one or more pathways that are involved in responding to or repairing damaged DNA. In this review, we discuss these pathways in relationship to a large number of studies performed with MDS patient samples and MDS mouse models. Moreover, in view of our current understanding of how DNA damage response and repair pathways are affected by age in hematopoietic stem cells, we also explore how this might relate to MDS development.

Figure 1. A working model of the generation of MDS-initiating cells (MDS-ICs) and AML-initiating cells (AML-ICs)

First, normal HSCs become MDS-ICs through the acquisition of gene mutations that result in abnormal differentiation. Next, additional gene mutations, subsequently acquired in the same MDS-IC or its progeny, confer a significant proliferative advantage of the dysplastic cells, which can then transform into AML-ICs.

Figure 2. Ageing-related accumulation of DSBs in mouse (A) and human (B) stem/progenitor populations

The figure is drawn with data adapted from previous publications [90, 106]. DSBs were visualized by immunostaining of γ-H2AX. (A) Percentage of γ-H2AX-positive cells in the indicated cell populations isolated from 10-week-old (black circles) and 122-week-old mice (open circles). (B) The number of γ-H2AX-foci per cell was counted in the indicated cell populations isolated from cord blood (black circles) and 70-year-old healthy elderly (open circles).