Therapeutic Modulation of DNA Damage and Repair Mechanisms in Blood Cells

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