Oxidized mitochondrial DNA released after inflammasome activation is a disease biomarker for myelodysplastic
Grace A Ward1, Kathy L McGraw2, Farnoosh Abbas-Aghababazadeh3
1Cancer Biology PhD Program, University of South Florida and H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.
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.
Insights
Oxidized mitochondrial DNA (ox-mtDNA) is a novel biomarker for myelodysplastic syndromes (MDS). Elevated ox-mtDNA levels in patient plasma indicate pyroptotic cell death and aid in MDS diagnosis and risk stratification.
Area of Science:
- Hematology
- Immunology
- Molecular Biology
Background:
- Myelodysplastic syndromes (MDS) are stem cell malignancies that mimic other blood disorders, necessitating improved diagnostic tools.
- Innate immune activation, specifically NLRP3-inflammasome-mediated pyroptosis, drives ineffective hematopoiesis in MDS.
- Oxidized mitochondrial DNA (ox-mtDNA) released during cell death acts as a danger signal, activating inflammasomes.
Purpose of the Study:
- To investigate if ox-mtDNA can serve as a diagnostic and prognostic biomarker in myelodysplastic syndromes.
- To correlate ox-mtDNA levels with disease risk and pyroptotic cell death markers in MDS patients.
Main Methods:
- Analysis of ox-mtDNA levels in plasma from murine MDS models and human MDS patient samples.
- Comparison of ox-mtDNA levels in MDS patients versus healthy donors and other hematologic malignancies.
- Correlation analysis of ox-mtDNA with alarmins (S100A9, S100A8) and CARD specks as indicators of pyroptosis.
Main Results:
- Oxidized mitochondrial DNA (ox-mtDNA) was significantly increased in MDS plasma compared to healthy donors.
- Higher ox-mtDNA levels were observed in lower-risk MDS compared to higher-risk MDS, correlating with pyroptosis.
- Ox-mtDNA demonstrated high sensitivity and specificity as a biomarker for MDS (AUC > 0.89), distinguishing it from other hematologic malignancies, except CLL.
- Ox-mtDNA levels positively correlated with established pyroptosis markers.
Conclusions:
- Quantifiable ox-mtDNA released during inflammasome activation is a sensitive and specific biomarker for MDS.
- Ox-mtDNA levels reflect the extent of pyroptotic cell death in MDS, aiding in diagnosis and risk assessment.
- This finding offers a novel tool to complement current diagnostic practices for myelodysplastic syndromes.
