Oxidized mitochondrial DNA released after inflammasome activation is a disease biomarker for myelodysplastic syndromes

Abstract

Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem cell malignancies that can phenotypically resemble other hematologic disorders. Thus, tools that may add to current diagnostic practices could aid in disease discrimination. Constitutive innate immune activation is a pathogenetic driver of ineffective hematopoiesis in MDS through Nod-like receptor protein 3 (NLRP3)–inflammasome-induced pyroptotic cell death. Oxidized mitochondrial DNA (ox-mtDNA) is released upon cytolysis, acts as a danger signal, and triggers inflammasome oligomerization via DNA sensors. By using immortalized bone marrow cells from murine models of common MDS somatic gene mutations and MDS primary samples, we demonstrate that ox-mtDNA is released upon pyroptosis. ox-mtDNA was significantly increased in MDS peripheral blood (PB) plasma compared with the plasma of healthy donors, and it was significantly higher in lower-risk MDS vs higher-risk MDS, consistent with the greater pyroptotic cell fraction in lower-risk patients. Furthermore, ox-mtDNA was significantly higher in MDS PB plasma compared with all other hematologic malignancies studied, with the exception of chronic lymphocytic leukemia (CLL). Receiver operating characteristic/area under the curve (ROC/AUC) analysis demonstrated that ox-mtDNA is a sensitive and specific biomarker for patients with MDS compared with healthy donors (AUC, 0.964), other hematologic malignancies excluding CLL (AUC, 0.893), and reactive conditions (AUC, 0.940). ox-mtDNA positively and significantly correlated with levels of known alarmins S100A9, S100A8, and apoptosis-associated speck-like protein containing caspase recruitment domain (CARD) specks, which provide an index of medullary pyroptosis. Collectively, these data indicate that quantifiable ox-mtDNA released into the extracellular space upon inflammasome activation serves as a biomarker for MDS and the magnitude of pyroptotic cell death.

Nature or Nurture? Role of the Bone Marrow Microenvironment in the Genesis and Maintenance of Myelodysplastic Syndromes

“…Recent data have suggested that damage-associated molecular pattern (DAMP)induced inflammation (via oxidized mitochondrial DNA) in the BM of MDS patients can lead to the uncontrolled activation of inflammasome machinery, causing HPSC lytic cell death mediated via pyroptosis, and this can act as a pathogenetic driver of ineffective haematopoiesis in MDS (Figure 2). The levels of oxidized mitochondrial DNA were reported to be highest in MDS compared with other overlapping syndromes and reactive conditions, such as CMML, ChIP, and anaemia [176]. Furthermore, mesenchymal niche can also induce genotoxic stress through p53-S100A8/9-TLR4 inflammatory signalling pathway which directly induces mitochondrial dysfunction, oxidative stress, and the activation of DNA damage responses in HSPCs159.…”

Role of Mitochondrial Nucleic Acid Sensing Pathways in Health and Patho-Physiology

“…This clearly indicates a great potential for developing or re-tasking drugs for treating these systemic inflammatory diseases associated with mitochondrial energetics and metabolism. Additionally, new biomarkers of the mitochondrial nucleic acid sensing pathways could accelerate timely detection and life-saving therapeutic interventions (Borsche et al, 2020;Ward et al, 2021). Hence, it is necessary to have a comprehensive overview of the mitochondrial nucleic acid sensing pathways in order to study diseases of the OXPHOS dysfunction.…”

Molecular Mechanisms of mtDNA-Mediated Inflammation

“…As re-introduced oxidized DNA can activate NLRP3 regardless of its origin, it is likely that NLRP3 senses the presence of 8-OH-dG within ox-mtDNA. Ward et al reported an increased secretion of ox-mtDNA, following inflammasome activation in an in vitro cancer model [ 49 ].…”