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Self-renewing hematopoietic stem cells and multipotent progenitor cells are responsible for maintaining hematopoiesis throughout an individual's lifetime. For overall health and survival, it is critical that the genome stability of these cells is maintained and that the cell population is not exhausted. Previous reports have indicated that the DEK protein, a chromatin structural protein that functions in numerous nuclear processes, is required for DNA damage repair in vitro and long-term engraftment of hematopoietic stem cells in vivo. Therefore, we investigated the role of DEK in normal hematopoiesis and response to DNA damaging agents in vivo. Here, we report that hematopoiesis is largely unperturbed in DEK knockout mice compared with wild-type (WT) controls. However, DEK knockout mice have fewer radioprotective units, but increased capacity to survive repeated sublethal doses of radiation exposure compared with WT mice. Furthermore, this increased survival correlated with a sustained quiescent state in which DEK knockout restricted hematopoietic progenitor cells (HPC-1) were nearly three times more likely to be quiescent following irradiation compared with WT cells and were significantly more radioresistant during the early phases of myeloid reconstitution. Together, our studies indicate that DEK functions in the normal hematopoietic stress response to recurrent radiation exposure., (Copyright © 2018 ISEH – Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Aging in the hematopoietic system and the stem cell niche contributes to aging-associated phenotypes of hematopoietic stem cells (HSCs), including leukemia and aging-associated immune remodeling. Among others, the DNA damage theory of aging of HSCs is well established, based on the detection of a significantly larger amount of γH2AX foci and a higher tail moment in the comet assay, both initially thought to be associated with DNA damage in aged HSCs compared with young cells, and bone marrow failure in animals devoid of DNA repair factors. Novel data on the increase in and nature of DNA mutations in the hematopoietic system with age, the quality of the DNA damage response in aged HSCs, and the nature of γH2AX foci question a direct link between DNA damage and the DNA damage response and aging of HSCs, and rather favor changes in epigenetics, splicing-factors or three-dimensional architecture of the cell as major cell intrinsic factors of HSCs aging. Aging of HSCs is also driven by a strong contribution of aging of the niche. This review discusses the DNA damage theory of HSC aging in the light of these novel mechanisms of aging of HSCs., (Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)

Haematopoietic stem cells (HSCs) are responsible for the lifelong production of blood cells. The accumulation of DNA damage in HSCs is a hallmark of ageing and is probably a major contributing factor in age-related tissue degeneration and malignant transformation. A number of accelerated ageing syndromes are associated with defective DNA repair and genomic instability, including the most common inherited bone marrow failure syndrome, Fanconi anaemia. However, the physiological source of DNA damage in HSCs from both normal and diseased individuals remains unclear. Here we show in mice that DNA damage is a direct consequence of inducing HSCs to exit their homeostatic quiescent state in response to conditions that model physiological stress, such as infection or chronic blood loss. Repeated activation of HSCs out of their dormant state provoked the attrition of normal HSCs and, in the case of mice with a non-functional Fanconi anaemia DNA repair pathway, led to a complete collapse of the haematopoietic system, which phenocopied the highly penetrant bone marrow failure seen in Fanconi anaemia patients. Our findings establish a novel link between physiological stress and DNA damage in normal HSCs and provide a mechanistic explanation for the universal accumulation of DNA damage in HSCs during ageing and the accelerated failure of the haematopoietic system in Fanconi anaemia patients.

Chromosomal translocation (8;21) is present in 10% to 15% of patients with acute myeloid leukemia. Expression of the AML1-ETO (AE) fusion protein alone is not sufficient to induce leukemia, but the nature of the additional genetic alterations is unknown. It is unclear whether AE facilitates acquisition of these cooperating events. We show that AE down-regulates genes involved in multiple DNA repair pathways, potentially through a mechanism involving direct binding at promoter elements, and increases the mutation frequency in vivo. AE cells display increased DNA damage in vitro and have an activated p53 pathway. This results in increased basal apoptosis and enhanced sensitivity to DNA damaging agents. Intriguingly, microarray data indicate that t(8;21) patient samples exhibit decreased expression of DNA repair genes and increased expression of p53 response genes compared with other acute myeloid leukemia (AML) patient samples. Inhibition of the p53 pathway by RNAi increases the resistance of AE cells to DNA damage. We thus speculate that AML1-ETO may facilitate accumulation of genetic alterations by suppressing endogenous DNA repair. It is possible that the superior outcome of t(8;21) patients is partly due to an activated p53 pathway, and that loss of the p53 response pathway is associated with disease progression.

Aging is associated with reduced organ function and increased disease incidence. Hematopoietic stem cell (HSC) aging driven by both cell intrinsic and extrinsic factors is linked to impaired HSC self-renewal and regeneration, aging-associated immune remodeling, and increased leukemia incidence. Compromised DNA damage responses and the increased production of reactive oxygen species (ROS) have been previously causatively attributed to HSC aging. However, recent paradigm-shifting concepts, such as global epigenetic and cytoskeletal polarity shifts, cellular senescence, as well as the clonal selection of HSCs upon aging, provide new insights into HSC aging mechanisms. Rejuvenating agents that can reprogram the epigenetic status of aged HSCs or senolytic drugs that selectively deplete senescent cells provide promising translational avenues for attenuating hematopoietic aging and, potentially, alleviating aging-associated immune remodeling and myeloid malignancies. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cells (HSCs) generate all known hematopoietic lineages and self-renew, but the function of HSCs declines during aging, which is characterized as impairments of lymphopoiesis and enhanced myelopoiesis. These aging-associated changes correlate with an increasing risk of myelo-proliferative diseases and impairments in immune function. Recent studies showed that only a subpopulation of HSCs contains a high capacity to undergo lymphoid differentiation but this subpopulation is lost during aging, which contributes to age-related impairments in lymphopoiesis. On the basis of the observations that DNA damage and telomere dysfunction can impair stem cell function, it is possible that accumulation of DNA damage results in the loss of subpopulations of HSCs that are required for the maintenance of lymphopoiesis and immune functions during aging. [ABSTRACT FROM AUTHOR]