Resilient and resourceful: Genome maintenance strategies in hematopoietic stem cells

Abstract

Blood homeostasis is maintained by a rare population of quiescent hematopoietic stem cells (HSC), which self-renew and differentiate to give rise to all lineages of mature blood cells. In contrast to most other blood cells, HSCs are preserved throughout life and maintenance of their genomic integrity is therefore paramount to ensure normal blood production and prevent leukemic transformation. HSCs are also one of the few blood cells that truly age and exhibit severe functional decline in old organisms, resulting in impaired blood homeostasis and increased risk for hematological malignancies. In this review, we present the strategies used by HSCs to cope with the many genotoxic insults that they commonly encounter. We briefly describe the DNAdamaging insults that can affect HSC function, and the mechanisms that are employed by HSCs to prevent, survive, and repair DNA lesions. We also discuss an apparent paradox in HSC biology, in which the genome maintenance strategies used by HSCs to protect their function in fact render them vulnerable to the acquisition of damaging genetic aberrations.

Normal and Leukemic Stem Cell Niches: Insights and Therapeutic Opportunities

“…Finally, cell-bound molecules like Notch ligands or locally secreted cytokines like interleukin 7 (IL-7) or erythropoietin (EPO) are important controllers of HSC proliferation and differentiation activity. In adult bones, HSCs are essentially kept in the G 0 phase of the cell cycle in a stage of metabolic dormancy or quiescence, which preserves their function by limiting damage associated with cell replication (Bakker and Passegué, 2013). However, quiescent HSCs can quickly respond to a broad range of niche or systemic signals by entering the cell cycle and proliferating (Pietras et al, 2011).…”

“…HSCs are constantly exposed to both intrinsic and extrinsic stresses, which can cause DNA damage and lead to mutations if not properly resolved (Bakker and Passegué, 2013). These mutations accumulate with age and can result in malignant transformation (Welch et al, 2012).…”

Haematopoietic and immune defects associated with GATA2 mutation

“…The absence of MLP/LMPP, loss of lymphoid and monocyte/DC haematopoiesis, with relative sparing of erythropoiesis and granulopoiesis, resembles an accelerated ageing phenotype (Gekas & Graf, 2013). It will be of interest to determine whether objective signs of this can be detected prematurely in GATA2 patients (Bakker & Passegue, 2013).…”

ICL-induced miR139-3p and miR199a-3p have opposite roles in hematopoietic cell expansion and leukemic transformation

“…2 Ineffective repair of DNA damage is one of the major causes of BMF and leukemic transformation. 3 Fanconi anemia (FA) is the most frequently inherited cause of BMF. 4 Defective interstrand crosslink (ICL) repair is a major hallmark of FA.…”