Oxidative DNA Damage, Inflammatory Signature, and Altered Erythrocytes Properties in Diamond-Blackfan Anemia

Abstract

Molecular pathophysiology of Diamond-Blackfan anemia (DBA) involves disrupted erythroid-lineage proliferation, differentiation and apoptosis; with the activation of p53 considered as a key component. Recently, oxidative stress was proposed to play an important role in DBA pathophysiology as well. CRISPR/Cas9-created Rpl5- and Rps19-deficient murine erythroleukemia (MEL) cells and DBA patients’ samples were used to evaluate proinflammatory cytokines, oxidative stress, DNA damage and DNA damage response. We demonstrated that the antioxidant defense capacity of Rp-mutant cells is insufficient to meet the greater reactive oxygen species (ROS) production which leads to oxidative DNA damage, cellular senescence and activation of DNA damage response signaling in the developing erythroblasts and altered characteristics of mature erythrocytes. We also showed that the disturbed balance between ROS formation and antioxidant defense is accompanied by the upregulation of proinflammatory cytokines. Finally, the alterations detected in the membrane of DBA erythrocytes may cause their enhanced recognition and destruction by reticuloendothelial macrophages, especially during infections. We propose that the extent of oxidative stress and the ability to activate antioxidant defense systems may contribute to high heterogeneity of clinical symptoms and response to therapy observed in DBA patients.

Effect of Glucocorticosteroids in Diamond-Blackfan Anaemia: Maybe Not as Elusive as It Seems

“…As mentioned above, in addition to ribosomal stress, p53 could be activated by HEMmediated ROS production [60,61]. Although it has been reported that GCs reduce ROS species [62][63][64], their overall influence on ROS production is ambiguous [65].…”

“…More specifically, it seems that short-term GC usage leads to a reduction in ROS generation, whereas long-term exposure leads to ROS induction [65]. Furthermore, increased ROS levels have been detected in DBA patients regardless of treatment [60]. Therefore, GC-mediated p53 regulation does not seem to reflect ROS levels.…”

“…In DBA, autophagy is increased despite mTOR activation [13]. It seems to be induced by ROS [60], hypoxia [87] or some mTOR-independent pathways [88]. However, mTORindependent autophagy may not be sufficient for proper RBC development [89].…”

Bone Marrow Failure Syndromes, Overlapping Diseases with a Common Cytokine Signature

“…Whether cytokines are drivers or passengers in BMF development is still an open question. Indeed, prolonged in vitro exposure to TNFα and IFNγ can induce senescence through increased oxidative stress, reactive oxygen species (ROS) production, and DNA damage, as also recently described in DBA [145,146]. Oxidative stress and DNA damage are generated by IL1β and TGFβ persistent stimulation.…”

Mechanism of Saffron Extract against Cardiotoxicity Induced by Doxorubicin: 4D Label-Free Quantitative proteomics Analysis and Bioinformatic Study

“…Moreover, damaged or mutated ribosomal proteins can mediate oxidative stress. It has been demonstrated that increased levels of reactive oxygen species (ROS) have been detected in RPL5-and RPS19-de cient Diamond-Blackfan anemia (DBA) mouse cell models [37]. Thus, the disruption of ribosome assembly increases ROS production, thereby leading to an oxidative and translational defective cellular "snowball" effect that may further enhance the mutagenic phenotype [34].…”