Therapeutic Modulation of DNA Damage and Repair Mechanisms in Blood Cells

Hematopoietic stem cells (HSCs) are a rare population of pluripotent cells that predominantly reside in the bone marrow. Under the appropriate microenvironmental cues, HSCs can undergo self-renewal, expansion, and differentiation into all types of progenitor and terminally differentiated blood cells required for survival of the host (Figure 1). Due to the importance of this cell population for survival, protection of its genome from endogenous and exogenous genotoxic insults is a necessity. However, the intracellular molecular signaling network in hematopoietic cells that control surveillance of the genome as well as maintain genome stability is still largely unexplored. As more is learned regarding how these cells detect a genotoxic event and seek to repair the damaged nucleotides (i.e. DNA adducts), it will become even more feasible to design strategies to protect these life-sustaining cells when the host is exposed to a genotoxic event. Maintenance of genome stability in both the hematopoietic stem and progenitor cell (HSPC) populations is essential for the sustainment of normal hematopoiesis. For example, transient depletion of bone-marrow derived HSC induced by irradiation or chemotherapy can induce these primitive cells to expand so that the bone marrow can be fully reconstituted; blood-cell development can then continue with minimal disruption. However, once therapy-mediated DNA damage is too high, a DNA-damage threshold is reached resulting in subsequent cell death, myelosuppression, and if not treated, life-threatening bone-marrow failure (Figure 1). With the basal level of DNA repair relatively low in these cells, this does present a challenge to maintain normal hematopoiesis in individuals exposed to prolonged or high levels of genotoxic stress. The reduced ability to repair DNA damage in HSPCs that give rise to multiple mature blood-cell lineages can cause detrimental and long-lasting effects to the host resulting in abnormal cell function, cell death, cellular transformation, and eventually leukemogenesis (Figure 1). Numerous studies have shown that HSPCs are intrinsically more sensitive than other cell types and tissues mostly due to intrinsic limitations in DNA-repair capacity. Buschfort-Papewalis et al previously demonstrated that when human HSPCs (phenotypically defined as CD34+ cells) or differentiated cells (phenotypically defined as CD34cells) from the same donor were exposed to alkylating agents, an overall decrease in repair capacity of the more primitive CD34+ cells compared the more differentiated cells CD34cells was observed. When human CD34+ cells were exposed to a variety of chemotherapeutic drugs, single-strand DNA breaks as well as DNA adducts were found at higher levels and persisted for longer time periods than in CD34cells (Buschfort-Papewalis et al., 2002), providing evidence that the kinetics of DNA repair are slower overall in the